Kanserde Terapötik Hedef Olarak Axl Reseptörü ve Axl İnhibitörleri
Özet
Kanser hücrelerinde ve tümör mikro çevresinde bazı sinyal yolu düzensizlikleri sıkça gözlenmekte ve bu yolaklar ilaç geliştirmede önemli hedefler olmaktadır. Reseptör Tirozin Kinaz (RTK)’lardaki anormal işleyişler de birçok malignitede tespit edilmiştir. Bir RTK üyesi olan AXL’ın aşırı ekspresyonu da kanserde kötü prognozla ilişkilendirilmiştir. AXL kanserde, hücrenin hayatta kalması, EMT, metastaz ve terapötik direnç mekanizmalarında önemli rol oynar.
AXL, K vitaminine bağımlı protein ailesinde yer alan Büyüme Durdurma Spesifik Protein 6 (GAS6)’nın bağlanmasıyla aktive olur. GAS6/AXL sinyal yolu PI3K/AKT, MAPK/ERK ve STAT3 dahil olmak üzere aşağı akış yollarını aktive ederek kanserin ilerlemesini teşvik eder.
Kanser gelişiminin farklı süreçleriyle ilişkili bulunması, AXL'ı kemoterapötik hedef haline getirmiş ve AXL’a özgü pek çok terapötik ajan geliştirilmesinde etkili olmuştur. Son on yılda, TKI’ler, mAb’ler, ADC’ler ve çözünebilir reseptörler dahil olmak üzere bir dizi spesifik AXL hedefli tedavi, klinik gelişime dahil edilmiştir. Özellikle, AXL inhibitörleri ön çalışmalarda umut verici sonuçlar ortaya koymuştur. Gün geçtikçe artan araştırma sonuçları, AXL inhibisyonunu potansiyel kanser tedavi stratejilerinden biri yapmıştır. AXL inhibitörlerinin keşfi ve araştırılması, özellikle AXL’ın ilaç direncindeki etkinliğine dair kanıtların artmasıyla birlikte kritik önem taşımaktadır. Bu bölümde AXL’ın kanserde oynadığı rol kısaca anlatıldı ve AXL’ı hedef alan tedavi stratejilerinden AXL inhibitörleri tanıtılmıştır.
Some signaling pathway irregularities are frequently observed in cancer cells and the tumor microenvironment, and these pathways are important targets in drug development. The abnormal Receptor Tyrosine Kinase (RTK) function has also been detected in many malignancies. Overexpression of AXL, a RTK member, has also been associated with poor prognosis in cancer. AXL plays an important role in cell survival, EMT, metastasis and therapeutic resistance mechanisms in cancer.
AXL is activated by binding to Growth Arrest Specific Protein 6 (GAS6), which belongs to the vitamin K-dependent protein family. The GAS6/AXL signaling pathway promotes cancer progression by activating downstream pathways including PI3K/AKT, MAPK/ERK, and STAT3.
Its association with different processes of cancer development has made AXL a chemotherapeutic target and has been effective in the development of many AXL-specific therapeutic agents. Over the past decade, a number of specific AXL-targeted therapies have been introduced into clinical development, including TKIs, mAbs, ADCs, and soluble receptors. In particular, AXL inhibitors have demonstrated promising results in preliminary studies. Increasing research results have made AXL inhibition one of the potential cancer treatment strategies. The discovery and research of AXL inhibitors is critical, especially as evidence increases for the effectiveness of AXL in drug resistance. In this section, the role of AXL in cancer is briefly explained and AXL inhibitors, one of the treatment strategies targeting AXL, are introduced.
Referanslar
Antony J, Huang RYJ. AXL-driven EMT state as a targetable conduit in cancer, Cancer Res. 2017; 77 (14) 3725–3732.
Liu E, Hjelle B, Bishop JM. Transforming genes in chronic myelogenous leukemia. Proc Natl Acad Sci U S A. 1988;85(6):1952-6. https:// doi. org/ 10. 1073/ pnas. 85.6. 1952
Di Stasi R, De Rosa L, D'Andrea LD. Therapeutic aspects of the Axl/Gas6 molecular system. Drug Discov Today. 2020 Dec;25(12):2130-2148. doi: 10.1016/j.drudis.2020.09.022. Epub 2020 Sep 28. PMID: 33002607.
Mudduluru, G. Axl and its mediated Signaling Axis in cancer. Johannes Haybaeck (Ed.), Mechanisms of molecular carcinogenesis. Switzerland: Springer International Publishing. 2017; 39-60.
Levin PA, Brekken RA, Byers LA, Heymach JV, Gerber DE. Axl receptor axis: a new therapeutic target in lung cancer. J Thorac Oncol. 2016;11(8):1357–62. https:// doi. org/ 10. 1016/j. jtho. 2016. 04. 015.
Lemke G, Rothlin CV. Immunobiology of the TAM receptors, Nat. Rev. Immunol. 8 (5) (2008) 327–336.
Scaltriti M, Elkabets M, Baselga J. Molecular Pathways: AXL, a membrane receptor mediator of resistance to therapy. Clin Cancer Res. 2016;22(6):1313–7. https:// doi. org/ 10. 1158/ 1078-0 432. CCR- 15- 1458.
Gay CM, Balaji K, Byers LA. Giving AXL the axe: targeting AXL in human malignancy. Br J Cancer. 2017;116(4):415–23. https:// doi. org/ 10. 1038/ bjc. 2016. 428.
Zhu C, Wei Y, Wei X. AXL receptor tyrosine kinase as a promising anti-cancer approach: functions, molecular mechanisms and clinical applications. Mol Cancer. 2019;18(1):153. https:// doi.org/ 10. 1186/ s12943- 019- 1090-3.
Atıcı Y. ve Kara H. (2022) Bölüm 9 “Gas6/Axl Sinyal Yolu ve Kanserle İlişkisi”, Güncel Biyokimya Çalışmaları III, Editör Doğan YÜCEL, Akademisyen Yayınevi, Ankara
Son HY, Jeong HK. Immune Evasion Mechanism and AXL. Front Oncol. 2021 Oct 28;11:756225. doi: 10.3389/fonc.2021.756225. PMID: 34778071; PMCID: PMC8581356.
Zhang G, Kong X, Wang M, Zhao H, Han S, Hu R, et al. AXL is a marker for epithelial-mesenchymal transition in esophageal squamous cell carcinoma. Oncol Lett. 2018;15(2):1900–6.https:// doi. org/ 10. 3892/ ol. 2017. 7443.
Bhalla S, Gerber DE. AXL Inhibitors: Status of Clinical Development. Curr Oncol Rep. 2023 May;25(5):521-529. doi: 10.1007/s11912-023-01392-7. Epub 2023 Mar 15. PMID: 36920638.
Byers LA, Diao L, Wang J, Saintigny P, Girard L, Peyton M, et al. An epithelial-mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance.Clin Cancer Res. 2013;19(1):279–90. https:// doi. org/ 10. 1158/1078- 0432. CCR- 12- 1558.
Wu F, Li J, Jang C, Wang J, Xiong J. The role of Axl in drug resistance and epithelial-to-mesenchymal transition of non-small cell lung carcinoma. Int J Clin Exp Pathol. 2014 Sep 15;7(10):6653-61. PMID: 25400744; PMCID: PMC4230140.
Malvankar C, Kumar D. AXL kinase inhibitors- A prospective model for medicinal chemistry strategies in anticancer drug discovery. Biochim Biophys Acta Rev Cancer. 2022 Sep;1877(5):188786. doi: 10.1016/j.bbcan.2022.188786. Epub 2022 Sep 1. PMID: 36058379.
Zaman A, Bivona TG. Targeting AXL in NSCLC. Lung Cancer (Auckl). 2021 Aug 10;12:67-79. doi: 10.2147/LCTT.S305484. PMID: 34408519; PMCID: PMC8364399.
Lin JZ, Wang ZJ, De W, Zheng M, Xu WZ, Wu HF, et al. Targeting AXL overcomes resistance to docetaxel therapy in advanced prostate cancer. Oncotarget. 2017;8(25):41064–77. https:// doi.org/ 10. 18632/ oncot arget. 17026.
Taniguchi H, Yamada T, Wang R, Tanimura K, Adachi Y, Nishiyama A, et al. AXL confers intrinsic resistance to osimertinib and advances the emergence of tolerant cells. Nat Commun. 2019;10(1):259. https:// doi. org/ 10. 1038/ s41467-018-0 8074-0.
Hugo W, Zaretsky JM, Sun L, Song C, Moreno BH, Hu-Lieskovan S, et al. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell. 016;165(1):35–44. https:// doi. org/ 10. 1016/j. cell. 2016. 02. 065.
Auyez A, Sayan AE, Kriajevska M, Tulchinsky E. AXL Receptor in Cancer Metastasis and Drug Resistance: When Normal Functions Go Askew. Cancers (Basel). 2021 Sep 28;13(19):4864. doi: 10.3390/cancers13194864. PMID: 34638349; PMCID: PMC8507788.
Tanaka M, Siemann DW. Gas6/Axl signaling pathway in the tumor immune microenvironment. Cancers (Basel). 2020;12(7):1850. https:// doi. org/ 10. 3390/ cance rs120 71850.
Scott AM, Wolchok JD, Old LJ. Antibody therapy of cancer. Nat Rev Cancer. 2012;12(4):278–87. https:// doi. org/ 10. 1038/ nrc32 36.
Leconet W, Larbouret C, Chardes T, Thomas G, Neiveyans M, Busson M, et al. Preclinical validation of AXL receptor as a target for antibody-based pancreatic cancer immunotherapy. Oncogene. 2014;33(47):5405–14. https:// doi. org/ 10. 1038/ onc. 2013. 487.
Chang H, An R, Li X, Lang X, Feng J, Lv M. Anti-Axl monoclonal antibodies attenuate the migration of MDA-MB-231 breast cancer cells. Oncol Lett. 2021 Nov;22(5):749. doi: 10.3892/ol.2021.13010. Epub 2021 Aug 27.
Davra V, Kumar S, Geng K, Calianese D, Mehta D, Gadiyar V, Kasikara C, Lahey KC, Chang YJ, Wichroski M, Gao C, De Lorenzo MS, Kotenko SV, Bergsbaken T, Mishra PK, Gause WC, Quigley M, Spires TE, Birge RB. Axl and Mertk Receptors Cooperate to Promote Breast Cancer Progression by Combined Oncogenic Signaling and Evasion of Host Antitumor Immunity. Cancer Res. 2021 Feb 1;81(3):698-712. doi: 10.1158/0008-5472.CAN-20-2066. Epub 2020 Nov 25.
Van Renterghem B, Wozniak A, Castro PG, Franken P, Pencheva N, Sciot R, Schöffski P. Enapotamab Vedotin, an AXL-Specific Antibody-Drug Conjugate, Demonstrates Antitumor Efficacy in Patient-Derived Xenograft Models of Soft Tissue Sarcoma. Int J Mol Sci. 2022 Jul 6;23(14):7493. doi: 10.3390/ijms23147493.
Sharp LL, Chang C, Frey G, et al. Anti-tumor efficacy of BA3011, a novel conditionally active biologic (CAB) anti-AXLADC. Cancer Res. 2018;78(13_Supplement):827.
Zammarchi F, Havenith KE, Chivers S, Hogg P, Bertelli F, Tyrer P, Janghra N, Reinert HW, Hartley JA, van Berkel PH. Preclinical Development of ADCT-601, a Novel Pyrrolobenzodiazepine Dimer-based Antibody-drug Conjugate Targeting AXL-expressing Cancers. Mol Cancer Ther. 2022 Apr 1;21(4):582-593. doi: 10.1158/1535-7163.MCT-21-0715.
Mullen MM, Lomonosova E, Toboni MD, Oplt A, Cybulla E, Blachut B, Zhao P, Noia H, Wilke D, Rankin EB, Kuroki LM, Hagemann AR, Hagemann IS, McCourt CK, Thaker PH, Mutch DG, Powell MA, Mosammaparast N, Vindigni A, Fuh KC. GAS6/AXL Inhibition Enhances Ovarian Cancer Sensitivity to Chemotherapy and PARP Inhibition through Increased DNA Damage and Enhanced Replication Stress. Mol Cancer Res. 2022 Feb;20(2):265-279. doi: 10.1158/1541-7786.MCR-21-0302. Epub 2021 Oct 20.
Kariolis, M.S.; Miao, Y.R.; Jones, D.S., 2nd; Kapur, S.; Mathews, I.I.; Giaccia, A.J.; Cochran, J.R. An engineered Axl ‘decoy receptor’ effectively silences the Gas6-Axl signaling axis. Nat. Chem. Biol. 2014, 10, 977–983.
Tanaka M, Siemann DW. Therapeutic Targeting of the Gas6/Axl Signaling Pathway in Cancer. Int J Mol Sci. 2021 Sep 15;22(18):9953. doi: 10.3390/ijms22189953. PMID: 34576116; PMCID: PMC8469858.
Rankin, E.B.; Fuh, K.C.; Castellini, L.; Viswanathan, K.; Finger, E.C.; Diep, A.N.; LaGory, E.L.; Kariolis, M.S.; Chan, A.; Lindgren, D.; et al. Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET. Proc. Natl. Acad. Sci. USA 2014, 111, 13373–13378.
Xiao, Y.; Zhao, H.; Tian, L.; Nolley, R.; Diep, A.N.; Ernst, A.; Fuh, K.C.; Miao, Y.R.; von Eyben, R.; Leppert, J.T.; et al. S100A10 Is a Critical Mediator of GAS6/AXL-Induced Angiogenesis in Renal Cell Carcinoma. Cancer Res. 2019, 79, 5758–5768.
Zhao Z, Li Y, Liu W, Li X. Engineered IL-7 Receptor Enhances the Therapeutic Effect of AXL-CAR-T Cells on Triple-Negative Breast Cancer. Biomed Res Int. 2020 Jan 2;2020:4795171. doi: 10.1155/2020/4795171.
C. Wilson, X. Ye, T. Pham, E. Lin, S. Chan, E. McNamara, R.M. Neve, L. Belmont, H. Koeppen, R.L. Yauch, AXL inhibition sensitizes mesenchymal cancer cells to antimitotic drugs, Cancer Res. 74 (20) (2014) 5878–5890.
Sheridan C. First Axl inhibitor enters clinical trials. Nat Biotechnol. 2013 Sep;31(9):775-6. doi: 10.1038/nbt0913-775a.
Quinn JM, Greenwade MM, Palisoul ML, Opara G, Massad K, Guo L, Zhao P, Beck-Noia H, Hagemann IS, Hagemann AR, McCourt CK, Thaker PH, Powell MA, Mutch DG, Fuh KC. Therapeutic Inhibition of the Receptor Tyrosine Kinase AXL Improves Sensitivity to Platinum and Taxane in Ovarian Cancer. Mol Cancer Ther. 2019 Feb;18(2):389-398. doi: 10.1158/1535-7163.MCT-18-0537. Epub 2018 Nov 26.
Bhalla S, Farjana FJ, Williams JN, et al. Phase 1 dose escalation and expansion study of bemcentinib (BGB324), a firstin-class, selective AXL inhibitor, with docetaxel in patients with previously treated advanced NSCLC. J Clin Oncol. 2022;40(16_suppl):9081.
Shen Y, Chen X, He J, Liao D, Zu X. Axl inhibitors as novel cancer therapeutic agents. Life Sci. 2018 Apr 1;198:99-111. doi: 10.1016/j.lfs.2018.02.033. Epub 2018 Feb 27.
A. Mollard, S.L. Warner, L.T. Call, M.L. Wade, J.J. Bearss, A. Verma, S. Sharma, H. Vankayalapati, D.J. Bearss, Design, synthesis, and biological evaluation of a series of novel AXL kinase inhibitors, ACS Med. Chem. Lett. 2 (12) (2011) 907–912.
Aveic S, Corallo D, Porcù E, Pantile M, Boso D, Zanon C, Viola G, Sidarovich V, Mariotto E, Quattrone A, Basso G, Tonini GP. TP-0903 inhibits neuroblastoma cell growth and enhances the sensitivity to conventional chemotherapy. Eur J Pharmacol. 2018 Jan 5;818:435-448. doi: 10.1016/j.ejphar.2017.11.016. Epub 2017 Nov 14.
Wang D, Bi L, Ran J, Zhang L, Xiao N, Li X. Gas6/Axl signaling pathway promotes proliferation, migration and invasion and inhibits apoptosis in A549 cells. Exp Ther Med. 2021 Nov;22(5):1321. doi: 10.3892/etm.2021.10756. Epub 2021 Sep 20.
Terragno M, Vetrova A, Semenov O, Sayan AE, Kriajevska M, Tulchinsky E. Mesenchymal-epithelial transition and AXL inhibitor TP-0903 sensitise triple-negative breast cancer cells to the antimalarial compound, artesunate. Sci Rep. 2024 Jan 3;14(1):425. doi: 10.1038/s41598-023-50710-3.
Kim SH, Choi S, Lee WS. Bevacizumab and anexelekto inhibitor, TP-0903 inhibits TGF-β1-induced epithelial-mesenchymal transition of colon cancer cells. Anticancer Drugs. 2022 Jan 1;33(1):e453-e461. doi: 10.1097/CAD.0000000000001239.
Sinha S, Boysen J, Nelson M, Secreto C, Warner SL, Bearss DJ, et al. Targeted Axl inhibition primes chronic lymphocytic leukemia B cells to apoptosis and shows synergistic/additive effects in combination with BTK inhibitors. Clin Cancer Res. 2015;21(9):2115
Zhang Y, Arner EN, Rizvi A, Toombs JE, Huang H, Warner SL, Foulks JM, Brekken RA. AXL Inhibitor TP-0903 Reduces Metastasis and Therapy Resistance in Pancreatic Cancer. Mol Cancer Ther. 2022 Jan;21(1):38-47. doi: 10.1158/1535-7163.MCT-21-0293. Epub 2021 Oct 21.
Adjei AA, Melear J, Thompson J, et al. 536MO a phase I, firstin- human, safety, pharmacokinetic, and pharmacokinetic study of oral dubermatinib (TP-0903) in patients with advanced solid tumours. Ann Oncol. 2020;31(suppl_4):S469
Mims AS, Huang Y, Eisenmann E, et al. A phase 1b/2 study of TP-0903 and decitabine targeting mutant TP53 and/or complex karyotype in patients with untreated acute myeloid leukemia ≥ age 60 years: phase 1b interim results. J Clin Oncol. 2022;40(16_suppl):9081.
Jeon JY, Buelow DR, Garrison DA, Niu M, Eisenmann ED, Huang KM, Zavorka Thomas ME, Weber RH, Whatcott CJ, Warner SL, Orwick SJ, Carmichael B, Stahl E, Brinton LT, Lapalombella R, Blachly JS, Hertlein E, Byrd JC, Bhatnagar B, Baker SD. TP-0903 is active in models of drug-resistant acute myeloid leukemia. JCI Insight. 2020 Dec 3;5(23):e140169. doi: 10.1172/jci.insight.140169.
Kostecki KL, Iida M, Wiley AL, Kimani S, Mehall B, Tetreault K, Alexandridis R, Yu M, Hong S, Salgia R, Bruce JY, Birge RB, Harari PM, Wheeler DL. Dual Axl/MerTK inhibitor INCB081776 creates a proinflammatory tumor immune microenvironment and enhances anti-PDL1 efficacy in head and neck cancer. Head Neck. 2023 May;45(5):1255-1271. doi: 10.1002/hed.27340. Epub 2023 Mar 20.
Rios-Doria J, Favata M, Lasky K, Feldman P, Lo Y, Yang G, Stevens C, Wen X, Sehra S, Katiyar K, Liu K, Wynn R, Harris JJ, Ye M, Spitz S, Wang X, He C, Li YL, Yao W, Covington M, Scherle P, Koblish H. A Potent and Selective Dual Inhibitor of AXL and MERTK Possesses Both Immunomodulatory and Tumor-Targeted Activity. Front Oncol. 2020 Dec 7;10:598477. doi: 10.3389/fonc.2020.598477.
Okura N, Nishioka N, Yamada T, Taniguchi H, Tanimura K, Katayama Y, Yoshimura A, Watanabe S, Kikuchi T, Shiotsu S, Kitazaki T, Nishiyama A, Iwasaku M, Kaneko Y, Uchino J, Uehara H, Horinaka M, Sakai T, Tanaka K, Kozaki R, Yano S, Takayama K. ONO-7475, a Novel AXL Inhibitor, Suppresses the Adaptive Resistance to Initial EGFR-TKI Treatment in EGFR-Mutated Non-Small Cell Lung Cancer. Clin Cancer Res. 2020 May 1;26(9):2244-2256. doi: 10.1158/1078-0432.CCR-19-2321. Epub 2020 Jan 17.
Post SM, Ma H, Malaney P, Zhang X, Aitken MJL, Mak PY, Ruvolo VR, Yasuhiro T, Kozaki R, Chan LE, Ostermann LB, Konopleva M, Carter BZ, DiNardo C, Andreeff MD, Khoury JD, Ruvolo PP. AXL/MERTK inhibitor ONO-7475 potently synergizes with venetoclax and overcomes venetoclax resistance to kill FLT3-ITD acute myeloid leukemia. Haematologica. 2022 Jun 1;107(6):1311-1322. doi: 10.3324/haematol.2021.278369. PMID: 34732043; PMCID: PMC9152975.
Mahadevan D, Theiss N, Morales C, Stejskal AE, Cooke LS, Zhu M, Kurtzman D, Swart R, Ong E, Qi W. Novel receptor tyrosine kinase targeted combination therapies for imatinib-resistant gastrointestinal stromal tumors (GIST). Oncotarget. 2015 Feb 10;6(4):1954-66. doi: 10.18632/oncotarget.3021..
Fedorenko IV, Fang B, Koomen JM, Gibney GT, Smalley KS. Amuvatinib has cytotoxic effects against NRAS-mutant melanoma but not BRAF-mutant melanoma. Melanoma Res. 2014 Oct;24(5):448-53. doi: 10.1097/CMR.0000000000000103. PMID: 24950457; PMCID: PMC4384823.
Dantas-Barbosa, C.; Lesluyes, T.; Loarer, F.L.; Chibon, F.; Treilleux, I.; Coindre, J.M.; Meeus, P.; Brahmi, M.; Bally, O.; Ray-Coquard, I.; et al. Expression and role of TYRO3 and AXL as potential therapeutical targets in leiomyosarcoma. Br. J. Cancer 2017, 117, 1787–1797.
Lin JJ, Choudhury NJ, Yoda S, Zhu VW, Johnson TW, Sakhtemani R, Dagogo-Jack I, Digumarthy SR, Lee C, Do A, Peterson J, Prutisto-Chang K, Malik W, Hubbeling HG, Langenbucher A, Schoenfeld AJ, Falcon CJ, Temel JS, Sequist LV, Yeap BY, Lennerz JK, Shaw AT, Lawrence MS, Ou SI, Hata AN, Drilon A, Gainor JF. Spectrum of Mechanisms of Resistance to Crizotinib and Lorlatinib in ROS1 Fusion-Positive Lung Cancer. Clin Cancer Res. 2021 May 15;27(10):2899-2909. doi: 10.1158/1078-0432.CCR-21-0032. Epub 2021 Mar 8.
Burbridge, M.F.; Bossard, C.J.; Saunier, C.; Fejes, I.; Bruno, A.; Leonce, S.; Ferry, G.; Da Violante, G.; Bouzom, F.; Cattan, V.; et al. S49076 is a novel kinase inhibitor of MET, AXL, and FGFR with strong preclinical activity alone and in association with bevacizumab. Mol. Cancer Ther. 2013, 12, 1749–1762. [CrossRef]
Viteri S, Chang G-C, Chiari R, Cho BC, Ciardiello F, Curigliano G, Hida T, Lee DH, Lim WTD, Lin C-C, Martinez A, Murakami H, Natsume I, Nishio M, Paz-Ares L, Soo RA, Cattan V, Gandossi E, Heck H, Park K. 1452P - Combination of the S49076 with gefitinib in NSCLC patients progressing on EGFR-TKI and harboring MET/AXL dysregulation, Annals of Oncology, Volume 29, Supplement 8, 2018, Page viii525, ISSN 0923-7534, https://doi.org/10.1093/annonc/mdy292.074.
Clemenson, C.; Chargari, C.; Liu,W.; Mondini, M.; Ferte, C.; Burbridge, M.F.; Cattan, V.; Jacquet-Bescond, A.; Deutsch, E. The MET/AXL/FGFR Inhibitor S49076 Impairs Aurora B Activity and Improves the Antitumor Efficacy of Radiotherapy. Mol. Cancer Ther. 2017, 16, 2107–2119.
Keunchil Park, Gee-Chen Chang, Giuseppe Curigliano, Wan-Teck Lim, Ross A. Soo, Miguel A. Molina-Vila, Valérie Cattan, Hélène Darville, Eric Gandossi, Veronika Smutna, Isabelle Sudey, Santiago Viteri, Phase I results of S49076 plus gefitinib in patients with EGFR TKI-resistant non-small cell lung cancer harbouring MET/AXL dysregulation, Lung Cancer, Volume 155, 2021, Pages 127-135, ISSN 0169-5002, https://doi.org/10.1016/j.lungcan.2021.03.012.
van der Mijn, J.C., Broxterman, H.J., Knol, J.C., Piersma, S.R., De Haas, R.R., Dekker, H., Pham, T.V., Van Beusechem, V.W., Halmos, B., Mier, J.W., Jiménez, C.R. and Verheul, H.M.W. (2016), Sunitinib activates Axl signaling in renal cell cancer. Int. J. Cancer, 138: 3002-3010. https://doi.org/10.1002/ijc.30022
Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, Pouliot F, Alekseev B, Soulières D, Melichar B, Vynnychenko I, Kryzhanivska A, Bondarenko I, Azevedo SJ, Borchiellini D, Szczylik C, Markus M, McDermott RS, Bedke J, Tartas S, Chang YH, Tamada S, Shou Q, Perini RF, Chen M, Atkins MB, Powles T; KEYNOTE-426 Investigators. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019 Mar 21;380(12):1116-1127. doi: 10.1056/NEJMoa1816714. Epub 2019 Feb 16.
Zhou L, Liu XD, Sun M, Zhang X, German P, Bai S, Ding Z, Tannir N, Wood CG, Matin SF, Karam JA, Tamboli P, Sircar K, Rao P, Rankin EB, Laird DA, Hoang AG, Walker CL, Giaccia AJ, Jonasch E. Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma. Oncogene. 2016 May;35(21):2687-97. doi: 10.1038/onc.2015.343. Epub 2015 Sep 14.
Msaouel P, Goswami S, Thall PF, Wang X, Yuan Y, Jonasch E, Gao J, Campbell MT, Shah AY, Corn PG, Tam AL, Ahrar K, Rao P, Sircar K, Cohen L, Basu S, Duan F, Jindal S, Zhang Y, Chen H, Yadav SS, Shazer R, Der-Torossian H, Allison JP, Sharma P, Tannir NM. A phase 1-2 trial of sitravatinib and nivolumab in clear cell renal cell carcinoma following progression on antiangiogenic therapy. Sci Transl Med. 2022 Apr 20;14(641):eabm6420. doi: 10.1126/scitranslmed.abm6420. Epub 2022 Apr 20.
Martinelli E, Martini G, Cardone C, Troiani T, Liguori G, Vitagliano D, Napolitano S, Morgillo F, Rinaldi B, Melillo RM, Liotti F, Nappi A, Bianco R, Berrino L, Ciuffreda LP, Ciardiello D, Iaffaioli V, Botti G, Ferraiolo F, Ciardiello F. AXL is an oncotarget in human colorectal cancer. Oncotarget. 2015 Sep 15;6(27):23281-96. doi: 10.18632/oncotarget.3962.
Chia, S.K.; Ellard, S.L.; Mates, M.; Welch, S.; Mihalcioiu, C.; Miller, W.H., Jr.; Gelmon, K.; Lohrisch, C.; Kumar, V.; Taylor, S.; et al. A phase-I study of lapatinib in combination with foretinib, a c-MET, AXL and vascular endothelial growth factor receptor inhibitor, in human epidermal growth factor receptor 2 (HER-2)-positive metastatic breast cancer. Breast Cancer Res. 2017, 19, 54.
Kataoka Y, Mukohara T, Tomioka H, Funakoshi Y, Kiyota N, Fujiwara Y, Yashiro M, Hirakawa K, Hirai M, Minami H. Foretinib (GSK1363089), a multi-kinase inhibitor of MET and VEGFRs, inhibits growth of gastric cancer cell lines by blocking inter-receptor tyrosine kinase networks. Invest New Drugs. 2012 Aug;30(4):1352-60. doi: 10.1007/s10637-011-9699-0. Epub 2011 Jun 8. PMID: 21655918.
Hassan MS, Williams F, Awasthi N, Schwarz MA, Schwarz RE, Li J, von Holzen U. Combination effect of lapatinib with foretinib in HER2 and MET co-activated experimental esophageal adenocarcinoma. Sci Rep. 2019 Nov 26;9(1):17608. doi: 10.1038/s41598-019-54129-7.
Liu, L.; Greger, J.; Shi, H.; Liu, Y.; Greshock, J.; Annan, R.; Halsey, W.; Sathe, G.M.; Martin, A.M.; Gilmer, T.M. Novel mechanism of lapatinib resistance in HER2-positive breast tumor cells: Activation of AXL. Cancer Res. 2009, 69, 6871–6878.
Yau TCC, Lencioni R, Sukeepaisarnjaroen W, Chao Y, Yen CJ, Lausoontornsiri W, Chen PJ, Sanpajit T, Camp A, Cox DS, Gagnon RC, Liu Y, Raffensperger KE, Kulkarni DA, Kallender H, Ottesen LH,
Yang, P.W.; Liu, Y.C.; Chang, Y.H.; Lin, C.C.; Huang, P.M.; Hua, K.T.; Lee, J.M.; Hsieh, M.S. Cabozantinib (XL184) and R428 (BGB324) Inhibit the Growth of Esophageal Squamous Cell Carcinoma (ESCC). Front. Oncol. 2019, 9, 1138.
Choueiri, T.K.; Powles, T.; Burotto, M.; Escudier, B.; Bourlon, M.T.; Zurawski, B.; Oyervides Juarez, V.M.; Hsieh, J.J.; Basso, U.; Shah, A.Y.; et al. Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N. Engl. J. Med. 2021, 384, 829–841.
Diane M. Bodenmiller, Julie A. Stewart, Glenn F. Evans, Victoria L. Peek, Jennifer R. Stephens, Xi Lin, Seema Iyer, Beverly L. Falcon, Sudhakar Chintharlapalli, Sau-Chi Betty Yan, Anthony S. Fischl. Characterization of the anti-angiogenic properties of merestinib (LY2801653), an oncokinase inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1823. doi:10.1158/1538-7445.AM2017-1823
Bruce W. Konicek, Steve M. Bray, Andrew R. Capen, John N. Calley, Kelly M. Credille, Philip J. Ebert, Gary Heady, Bharvin K. Patel, Victoria L. Peek, Jennifer R. Stephens, Suzane L. Um, Melinda D. Willard, Isabella H. Wulur, Yi Zeng, Richard A. Walgren, Sau-Chi Betty Yan. Merestinib (LY2801653), targeting several oncokinases including NTRK1/2/3, shows potent anti-tumor effect in colorectal cell line- and patient-derived xenograft (PDX) model bearing TPM3-NTRK1 fusion. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2647.
Zhu C, Shi H, Wu M, Wei X. A dual MET/AXL small-molecule inhibitor exerts efficacy against gastric carcinoma through killing cancer cells as well as modulating tumor microenvironment. MedComm. 2020; 1: 103–118. https://doi.org/10.1002/mco2.11
Kollmannsberger C, Hurwitz H, Bazhenova L, Cho BC, Hong D, Park K, Reckamp KL, Sharma S, Der-Torossian H, Christensen JG, Faltaos D, Potvin D, Tassell V, Chao R, Shapiro GI. Phase I Study Evaluating Glesatinib (MGCD265), An Inhibitor of MET and AXL, in Patients with Non-small Cell Lung Cancer and Other Advanced Solid Tumors. Target Oncol. 2023 Jan;18(1):105-118. doi: 10.1007/s11523-022-00931-9. Epub 2022 Dec 2.
Referanslar
Antony J, Huang RYJ. AXL-driven EMT state as a targetable conduit in cancer, Cancer Res. 2017; 77 (14) 3725–3732.
Liu E, Hjelle B, Bishop JM. Transforming genes in chronic myelogenous leukemia. Proc Natl Acad Sci U S A. 1988;85(6):1952-6. https:// doi. org/ 10. 1073/ pnas. 85.6. 1952
Di Stasi R, De Rosa L, D'Andrea LD. Therapeutic aspects of the Axl/Gas6 molecular system. Drug Discov Today. 2020 Dec;25(12):2130-2148. doi: 10.1016/j.drudis.2020.09.022. Epub 2020 Sep 28. PMID: 33002607.
Mudduluru, G. Axl and its mediated Signaling Axis in cancer. Johannes Haybaeck (Ed.), Mechanisms of molecular carcinogenesis. Switzerland: Springer International Publishing. 2017; 39-60.
Levin PA, Brekken RA, Byers LA, Heymach JV, Gerber DE. Axl receptor axis: a new therapeutic target in lung cancer. J Thorac Oncol. 2016;11(8):1357–62. https:// doi. org/ 10. 1016/j. jtho. 2016. 04. 015.
Lemke G, Rothlin CV. Immunobiology of the TAM receptors, Nat. Rev. Immunol. 8 (5) (2008) 327–336.
Scaltriti M, Elkabets M, Baselga J. Molecular Pathways: AXL, a membrane receptor mediator of resistance to therapy. Clin Cancer Res. 2016;22(6):1313–7. https:// doi. org/ 10. 1158/ 1078-0 432. CCR- 15- 1458.
Gay CM, Balaji K, Byers LA. Giving AXL the axe: targeting AXL in human malignancy. Br J Cancer. 2017;116(4):415–23. https:// doi. org/ 10. 1038/ bjc. 2016. 428.
Zhu C, Wei Y, Wei X. AXL receptor tyrosine kinase as a promising anti-cancer approach: functions, molecular mechanisms and clinical applications. Mol Cancer. 2019;18(1):153. https:// doi.org/ 10. 1186/ s12943- 019- 1090-3.
Atıcı Y. ve Kara H. (2022) Bölüm 9 “Gas6/Axl Sinyal Yolu ve Kanserle İlişkisi”, Güncel Biyokimya Çalışmaları III, Editör Doğan YÜCEL, Akademisyen Yayınevi, Ankara
Son HY, Jeong HK. Immune Evasion Mechanism and AXL. Front Oncol. 2021 Oct 28;11:756225. doi: 10.3389/fonc.2021.756225. PMID: 34778071; PMCID: PMC8581356.
Zhang G, Kong X, Wang M, Zhao H, Han S, Hu R, et al. AXL is a marker for epithelial-mesenchymal transition in esophageal squamous cell carcinoma. Oncol Lett. 2018;15(2):1900–6.https:// doi. org/ 10. 3892/ ol. 2017. 7443.
Bhalla S, Gerber DE. AXL Inhibitors: Status of Clinical Development. Curr Oncol Rep. 2023 May;25(5):521-529. doi: 10.1007/s11912-023-01392-7. Epub 2023 Mar 15. PMID: 36920638.
Byers LA, Diao L, Wang J, Saintigny P, Girard L, Peyton M, et al. An epithelial-mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance.Clin Cancer Res. 2013;19(1):279–90. https:// doi. org/ 10. 1158/1078- 0432. CCR- 12- 1558.
Wu F, Li J, Jang C, Wang J, Xiong J. The role of Axl in drug resistance and epithelial-to-mesenchymal transition of non-small cell lung carcinoma. Int J Clin Exp Pathol. 2014 Sep 15;7(10):6653-61. PMID: 25400744; PMCID: PMC4230140.
Malvankar C, Kumar D. AXL kinase inhibitors- A prospective model for medicinal chemistry strategies in anticancer drug discovery. Biochim Biophys Acta Rev Cancer. 2022 Sep;1877(5):188786. doi: 10.1016/j.bbcan.2022.188786. Epub 2022 Sep 1. PMID: 36058379.
Zaman A, Bivona TG. Targeting AXL in NSCLC. Lung Cancer (Auckl). 2021 Aug 10;12:67-79. doi: 10.2147/LCTT.S305484. PMID: 34408519; PMCID: PMC8364399.
Lin JZ, Wang ZJ, De W, Zheng M, Xu WZ, Wu HF, et al. Targeting AXL overcomes resistance to docetaxel therapy in advanced prostate cancer. Oncotarget. 2017;8(25):41064–77. https:// doi.org/ 10. 18632/ oncot arget. 17026.
Taniguchi H, Yamada T, Wang R, Tanimura K, Adachi Y, Nishiyama A, et al. AXL confers intrinsic resistance to osimertinib and advances the emergence of tolerant cells. Nat Commun. 2019;10(1):259. https:// doi. org/ 10. 1038/ s41467-018-0 8074-0.
Hugo W, Zaretsky JM, Sun L, Song C, Moreno BH, Hu-Lieskovan S, et al. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell. 016;165(1):35–44. https:// doi. org/ 10. 1016/j. cell. 2016. 02. 065.
Auyez A, Sayan AE, Kriajevska M, Tulchinsky E. AXL Receptor in Cancer Metastasis and Drug Resistance: When Normal Functions Go Askew. Cancers (Basel). 2021 Sep 28;13(19):4864. doi: 10.3390/cancers13194864. PMID: 34638349; PMCID: PMC8507788.
Tanaka M, Siemann DW. Gas6/Axl signaling pathway in the tumor immune microenvironment. Cancers (Basel). 2020;12(7):1850. https:// doi. org/ 10. 3390/ cance rs120 71850.
Scott AM, Wolchok JD, Old LJ. Antibody therapy of cancer. Nat Rev Cancer. 2012;12(4):278–87. https:// doi. org/ 10. 1038/ nrc32 36.
Leconet W, Larbouret C, Chardes T, Thomas G, Neiveyans M, Busson M, et al. Preclinical validation of AXL receptor as a target for antibody-based pancreatic cancer immunotherapy. Oncogene. 2014;33(47):5405–14. https:// doi. org/ 10. 1038/ onc. 2013. 487.
Chang H, An R, Li X, Lang X, Feng J, Lv M. Anti-Axl monoclonal antibodies attenuate the migration of MDA-MB-231 breast cancer cells. Oncol Lett. 2021 Nov;22(5):749. doi: 10.3892/ol.2021.13010. Epub 2021 Aug 27.
Davra V, Kumar S, Geng K, Calianese D, Mehta D, Gadiyar V, Kasikara C, Lahey KC, Chang YJ, Wichroski M, Gao C, De Lorenzo MS, Kotenko SV, Bergsbaken T, Mishra PK, Gause WC, Quigley M, Spires TE, Birge RB. Axl and Mertk Receptors Cooperate to Promote Breast Cancer Progression by Combined Oncogenic Signaling and Evasion of Host Antitumor Immunity. Cancer Res. 2021 Feb 1;81(3):698-712. doi: 10.1158/0008-5472.CAN-20-2066. Epub 2020 Nov 25.
Van Renterghem B, Wozniak A, Castro PG, Franken P, Pencheva N, Sciot R, Schöffski P. Enapotamab Vedotin, an AXL-Specific Antibody-Drug Conjugate, Demonstrates Antitumor Efficacy in Patient-Derived Xenograft Models of Soft Tissue Sarcoma. Int J Mol Sci. 2022 Jul 6;23(14):7493. doi: 10.3390/ijms23147493.
Sharp LL, Chang C, Frey G, et al. Anti-tumor efficacy of BA3011, a novel conditionally active biologic (CAB) anti-AXLADC. Cancer Res. 2018;78(13_Supplement):827.
Zammarchi F, Havenith KE, Chivers S, Hogg P, Bertelli F, Tyrer P, Janghra N, Reinert HW, Hartley JA, van Berkel PH. Preclinical Development of ADCT-601, a Novel Pyrrolobenzodiazepine Dimer-based Antibody-drug Conjugate Targeting AXL-expressing Cancers. Mol Cancer Ther. 2022 Apr 1;21(4):582-593. doi: 10.1158/1535-7163.MCT-21-0715.
Mullen MM, Lomonosova E, Toboni MD, Oplt A, Cybulla E, Blachut B, Zhao P, Noia H, Wilke D, Rankin EB, Kuroki LM, Hagemann AR, Hagemann IS, McCourt CK, Thaker PH, Mutch DG, Powell MA, Mosammaparast N, Vindigni A, Fuh KC. GAS6/AXL Inhibition Enhances Ovarian Cancer Sensitivity to Chemotherapy and PARP Inhibition through Increased DNA Damage and Enhanced Replication Stress. Mol Cancer Res. 2022 Feb;20(2):265-279. doi: 10.1158/1541-7786.MCR-21-0302. Epub 2021 Oct 20.
Kariolis, M.S.; Miao, Y.R.; Jones, D.S., 2nd; Kapur, S.; Mathews, I.I.; Giaccia, A.J.; Cochran, J.R. An engineered Axl ‘decoy receptor’ effectively silences the Gas6-Axl signaling axis. Nat. Chem. Biol. 2014, 10, 977–983.
Tanaka M, Siemann DW. Therapeutic Targeting of the Gas6/Axl Signaling Pathway in Cancer. Int J Mol Sci. 2021 Sep 15;22(18):9953. doi: 10.3390/ijms22189953. PMID: 34576116; PMCID: PMC8469858.
Rankin, E.B.; Fuh, K.C.; Castellini, L.; Viswanathan, K.; Finger, E.C.; Diep, A.N.; LaGory, E.L.; Kariolis, M.S.; Chan, A.; Lindgren, D.; et al. Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET. Proc. Natl. Acad. Sci. USA 2014, 111, 13373–13378.
Xiao, Y.; Zhao, H.; Tian, L.; Nolley, R.; Diep, A.N.; Ernst, A.; Fuh, K.C.; Miao, Y.R.; von Eyben, R.; Leppert, J.T.; et al. S100A10 Is a Critical Mediator of GAS6/AXL-Induced Angiogenesis in Renal Cell Carcinoma. Cancer Res. 2019, 79, 5758–5768.
Zhao Z, Li Y, Liu W, Li X. Engineered IL-7 Receptor Enhances the Therapeutic Effect of AXL-CAR-T Cells on Triple-Negative Breast Cancer. Biomed Res Int. 2020 Jan 2;2020:4795171. doi: 10.1155/2020/4795171.
C. Wilson, X. Ye, T. Pham, E. Lin, S. Chan, E. McNamara, R.M. Neve, L. Belmont, H. Koeppen, R.L. Yauch, AXL inhibition sensitizes mesenchymal cancer cells to antimitotic drugs, Cancer Res. 74 (20) (2014) 5878–5890.
Sheridan C. First Axl inhibitor enters clinical trials. Nat Biotechnol. 2013 Sep;31(9):775-6. doi: 10.1038/nbt0913-775a.
Quinn JM, Greenwade MM, Palisoul ML, Opara G, Massad K, Guo L, Zhao P, Beck-Noia H, Hagemann IS, Hagemann AR, McCourt CK, Thaker PH, Powell MA, Mutch DG, Fuh KC. Therapeutic Inhibition of the Receptor Tyrosine Kinase AXL Improves Sensitivity to Platinum and Taxane in Ovarian Cancer. Mol Cancer Ther. 2019 Feb;18(2):389-398. doi: 10.1158/1535-7163.MCT-18-0537. Epub 2018 Nov 26.
Bhalla S, Farjana FJ, Williams JN, et al. Phase 1 dose escalation and expansion study of bemcentinib (BGB324), a firstin-class, selective AXL inhibitor, with docetaxel in patients with previously treated advanced NSCLC. J Clin Oncol. 2022;40(16_suppl):9081.
Shen Y, Chen X, He J, Liao D, Zu X. Axl inhibitors as novel cancer therapeutic agents. Life Sci. 2018 Apr 1;198:99-111. doi: 10.1016/j.lfs.2018.02.033. Epub 2018 Feb 27.
A. Mollard, S.L. Warner, L.T. Call, M.L. Wade, J.J. Bearss, A. Verma, S. Sharma, H. Vankayalapati, D.J. Bearss, Design, synthesis, and biological evaluation of a series of novel AXL kinase inhibitors, ACS Med. Chem. Lett. 2 (12) (2011) 907–912.
Aveic S, Corallo D, Porcù E, Pantile M, Boso D, Zanon C, Viola G, Sidarovich V, Mariotto E, Quattrone A, Basso G, Tonini GP. TP-0903 inhibits neuroblastoma cell growth and enhances the sensitivity to conventional chemotherapy. Eur J Pharmacol. 2018 Jan 5;818:435-448. doi: 10.1016/j.ejphar.2017.11.016. Epub 2017 Nov 14.
Wang D, Bi L, Ran J, Zhang L, Xiao N, Li X. Gas6/Axl signaling pathway promotes proliferation, migration and invasion and inhibits apoptosis in A549 cells. Exp Ther Med. 2021 Nov;22(5):1321. doi: 10.3892/etm.2021.10756. Epub 2021 Sep 20.
Terragno M, Vetrova A, Semenov O, Sayan AE, Kriajevska M, Tulchinsky E. Mesenchymal-epithelial transition and AXL inhibitor TP-0903 sensitise triple-negative breast cancer cells to the antimalarial compound, artesunate. Sci Rep. 2024 Jan 3;14(1):425. doi: 10.1038/s41598-023-50710-3.
Kim SH, Choi S, Lee WS. Bevacizumab and anexelekto inhibitor, TP-0903 inhibits TGF-β1-induced epithelial-mesenchymal transition of colon cancer cells. Anticancer Drugs. 2022 Jan 1;33(1):e453-e461. doi: 10.1097/CAD.0000000000001239.
Sinha S, Boysen J, Nelson M, Secreto C, Warner SL, Bearss DJ, et al. Targeted Axl inhibition primes chronic lymphocytic leukemia B cells to apoptosis and shows synergistic/additive effects in combination with BTK inhibitors. Clin Cancer Res. 2015;21(9):2115
Zhang Y, Arner EN, Rizvi A, Toombs JE, Huang H, Warner SL, Foulks JM, Brekken RA. AXL Inhibitor TP-0903 Reduces Metastasis and Therapy Resistance in Pancreatic Cancer. Mol Cancer Ther. 2022 Jan;21(1):38-47. doi: 10.1158/1535-7163.MCT-21-0293. Epub 2021 Oct 21.
Adjei AA, Melear J, Thompson J, et al. 536MO a phase I, firstin- human, safety, pharmacokinetic, and pharmacokinetic study of oral dubermatinib (TP-0903) in patients with advanced solid tumours. Ann Oncol. 2020;31(suppl_4):S469
Mims AS, Huang Y, Eisenmann E, et al. A phase 1b/2 study of TP-0903 and decitabine targeting mutant TP53 and/or complex karyotype in patients with untreated acute myeloid leukemia ≥ age 60 years: phase 1b interim results. J Clin Oncol. 2022;40(16_suppl):9081.
Jeon JY, Buelow DR, Garrison DA, Niu M, Eisenmann ED, Huang KM, Zavorka Thomas ME, Weber RH, Whatcott CJ, Warner SL, Orwick SJ, Carmichael B, Stahl E, Brinton LT, Lapalombella R, Blachly JS, Hertlein E, Byrd JC, Bhatnagar B, Baker SD. TP-0903 is active in models of drug-resistant acute myeloid leukemia. JCI Insight. 2020 Dec 3;5(23):e140169. doi: 10.1172/jci.insight.140169.
Kostecki KL, Iida M, Wiley AL, Kimani S, Mehall B, Tetreault K, Alexandridis R, Yu M, Hong S, Salgia R, Bruce JY, Birge RB, Harari PM, Wheeler DL. Dual Axl/MerTK inhibitor INCB081776 creates a proinflammatory tumor immune microenvironment and enhances anti-PDL1 efficacy in head and neck cancer. Head Neck. 2023 May;45(5):1255-1271. doi: 10.1002/hed.27340. Epub 2023 Mar 20.
Rios-Doria J, Favata M, Lasky K, Feldman P, Lo Y, Yang G, Stevens C, Wen X, Sehra S, Katiyar K, Liu K, Wynn R, Harris JJ, Ye M, Spitz S, Wang X, He C, Li YL, Yao W, Covington M, Scherle P, Koblish H. A Potent and Selective Dual Inhibitor of AXL and MERTK Possesses Both Immunomodulatory and Tumor-Targeted Activity. Front Oncol. 2020 Dec 7;10:598477. doi: 10.3389/fonc.2020.598477.
Okura N, Nishioka N, Yamada T, Taniguchi H, Tanimura K, Katayama Y, Yoshimura A, Watanabe S, Kikuchi T, Shiotsu S, Kitazaki T, Nishiyama A, Iwasaku M, Kaneko Y, Uchino J, Uehara H, Horinaka M, Sakai T, Tanaka K, Kozaki R, Yano S, Takayama K. ONO-7475, a Novel AXL Inhibitor, Suppresses the Adaptive Resistance to Initial EGFR-TKI Treatment in EGFR-Mutated Non-Small Cell Lung Cancer. Clin Cancer Res. 2020 May 1;26(9):2244-2256. doi: 10.1158/1078-0432.CCR-19-2321. Epub 2020 Jan 17.
Post SM, Ma H, Malaney P, Zhang X, Aitken MJL, Mak PY, Ruvolo VR, Yasuhiro T, Kozaki R, Chan LE, Ostermann LB, Konopleva M, Carter BZ, DiNardo C, Andreeff MD, Khoury JD, Ruvolo PP. AXL/MERTK inhibitor ONO-7475 potently synergizes with venetoclax and overcomes venetoclax resistance to kill FLT3-ITD acute myeloid leukemia. Haematologica. 2022 Jun 1;107(6):1311-1322. doi: 10.3324/haematol.2021.278369. PMID: 34732043; PMCID: PMC9152975.
Mahadevan D, Theiss N, Morales C, Stejskal AE, Cooke LS, Zhu M, Kurtzman D, Swart R, Ong E, Qi W. Novel receptor tyrosine kinase targeted combination therapies for imatinib-resistant gastrointestinal stromal tumors (GIST). Oncotarget. 2015 Feb 10;6(4):1954-66. doi: 10.18632/oncotarget.3021..
Fedorenko IV, Fang B, Koomen JM, Gibney GT, Smalley KS. Amuvatinib has cytotoxic effects against NRAS-mutant melanoma but not BRAF-mutant melanoma. Melanoma Res. 2014 Oct;24(5):448-53. doi: 10.1097/CMR.0000000000000103. PMID: 24950457; PMCID: PMC4384823.
Dantas-Barbosa, C.; Lesluyes, T.; Loarer, F.L.; Chibon, F.; Treilleux, I.; Coindre, J.M.; Meeus, P.; Brahmi, M.; Bally, O.; Ray-Coquard, I.; et al. Expression and role of TYRO3 and AXL as potential therapeutical targets in leiomyosarcoma. Br. J. Cancer 2017, 117, 1787–1797.
Lin JJ, Choudhury NJ, Yoda S, Zhu VW, Johnson TW, Sakhtemani R, Dagogo-Jack I, Digumarthy SR, Lee C, Do A, Peterson J, Prutisto-Chang K, Malik W, Hubbeling HG, Langenbucher A, Schoenfeld AJ, Falcon CJ, Temel JS, Sequist LV, Yeap BY, Lennerz JK, Shaw AT, Lawrence MS, Ou SI, Hata AN, Drilon A, Gainor JF. Spectrum of Mechanisms of Resistance to Crizotinib and Lorlatinib in ROS1 Fusion-Positive Lung Cancer. Clin Cancer Res. 2021 May 15;27(10):2899-2909. doi: 10.1158/1078-0432.CCR-21-0032. Epub 2021 Mar 8.
Burbridge, M.F.; Bossard, C.J.; Saunier, C.; Fejes, I.; Bruno, A.; Leonce, S.; Ferry, G.; Da Violante, G.; Bouzom, F.; Cattan, V.; et al. S49076 is a novel kinase inhibitor of MET, AXL, and FGFR with strong preclinical activity alone and in association with bevacizumab. Mol. Cancer Ther. 2013, 12, 1749–1762. [CrossRef]
Viteri S, Chang G-C, Chiari R, Cho BC, Ciardiello F, Curigliano G, Hida T, Lee DH, Lim WTD, Lin C-C, Martinez A, Murakami H, Natsume I, Nishio M, Paz-Ares L, Soo RA, Cattan V, Gandossi E, Heck H, Park K. 1452P - Combination of the S49076 with gefitinib in NSCLC patients progressing on EGFR-TKI and harboring MET/AXL dysregulation, Annals of Oncology, Volume 29, Supplement 8, 2018, Page viii525, ISSN 0923-7534, https://doi.org/10.1093/annonc/mdy292.074.
Clemenson, C.; Chargari, C.; Liu,W.; Mondini, M.; Ferte, C.; Burbridge, M.F.; Cattan, V.; Jacquet-Bescond, A.; Deutsch, E. The MET/AXL/FGFR Inhibitor S49076 Impairs Aurora B Activity and Improves the Antitumor Efficacy of Radiotherapy. Mol. Cancer Ther. 2017, 16, 2107–2119.
Keunchil Park, Gee-Chen Chang, Giuseppe Curigliano, Wan-Teck Lim, Ross A. Soo, Miguel A. Molina-Vila, Valérie Cattan, Hélène Darville, Eric Gandossi, Veronika Smutna, Isabelle Sudey, Santiago Viteri, Phase I results of S49076 plus gefitinib in patients with EGFR TKI-resistant non-small cell lung cancer harbouring MET/AXL dysregulation, Lung Cancer, Volume 155, 2021, Pages 127-135, ISSN 0169-5002, https://doi.org/10.1016/j.lungcan.2021.03.012.
van der Mijn, J.C., Broxterman, H.J., Knol, J.C., Piersma, S.R., De Haas, R.R., Dekker, H., Pham, T.V., Van Beusechem, V.W., Halmos, B., Mier, J.W., Jiménez, C.R. and Verheul, H.M.W. (2016), Sunitinib activates Axl signaling in renal cell cancer. Int. J. Cancer, 138: 3002-3010. https://doi.org/10.1002/ijc.30022
Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, Pouliot F, Alekseev B, Soulières D, Melichar B, Vynnychenko I, Kryzhanivska A, Bondarenko I, Azevedo SJ, Borchiellini D, Szczylik C, Markus M, McDermott RS, Bedke J, Tartas S, Chang YH, Tamada S, Shou Q, Perini RF, Chen M, Atkins MB, Powles T; KEYNOTE-426 Investigators. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019 Mar 21;380(12):1116-1127. doi: 10.1056/NEJMoa1816714. Epub 2019 Feb 16.
Zhou L, Liu XD, Sun M, Zhang X, German P, Bai S, Ding Z, Tannir N, Wood CG, Matin SF, Karam JA, Tamboli P, Sircar K, Rao P, Rankin EB, Laird DA, Hoang AG, Walker CL, Giaccia AJ, Jonasch E. Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma. Oncogene. 2016 May;35(21):2687-97. doi: 10.1038/onc.2015.343. Epub 2015 Sep 14.
Msaouel P, Goswami S, Thall PF, Wang X, Yuan Y, Jonasch E, Gao J, Campbell MT, Shah AY, Corn PG, Tam AL, Ahrar K, Rao P, Sircar K, Cohen L, Basu S, Duan F, Jindal S, Zhang Y, Chen H, Yadav SS, Shazer R, Der-Torossian H, Allison JP, Sharma P, Tannir NM. A phase 1-2 trial of sitravatinib and nivolumab in clear cell renal cell carcinoma following progression on antiangiogenic therapy. Sci Transl Med. 2022 Apr 20;14(641):eabm6420. doi: 10.1126/scitranslmed.abm6420. Epub 2022 Apr 20.
Martinelli E, Martini G, Cardone C, Troiani T, Liguori G, Vitagliano D, Napolitano S, Morgillo F, Rinaldi B, Melillo RM, Liotti F, Nappi A, Bianco R, Berrino L, Ciuffreda LP, Ciardiello D, Iaffaioli V, Botti G, Ferraiolo F, Ciardiello F. AXL is an oncotarget in human colorectal cancer. Oncotarget. 2015 Sep 15;6(27):23281-96. doi: 10.18632/oncotarget.3962.
Chia, S.K.; Ellard, S.L.; Mates, M.; Welch, S.; Mihalcioiu, C.; Miller, W.H., Jr.; Gelmon, K.; Lohrisch, C.; Kumar, V.; Taylor, S.; et al. A phase-I study of lapatinib in combination with foretinib, a c-MET, AXL and vascular endothelial growth factor receptor inhibitor, in human epidermal growth factor receptor 2 (HER-2)-positive metastatic breast cancer. Breast Cancer Res. 2017, 19, 54.
Kataoka Y, Mukohara T, Tomioka H, Funakoshi Y, Kiyota N, Fujiwara Y, Yashiro M, Hirakawa K, Hirai M, Minami H. Foretinib (GSK1363089), a multi-kinase inhibitor of MET and VEGFRs, inhibits growth of gastric cancer cell lines by blocking inter-receptor tyrosine kinase networks. Invest New Drugs. 2012 Aug;30(4):1352-60. doi: 10.1007/s10637-011-9699-0. Epub 2011 Jun 8. PMID: 21655918.
Hassan MS, Williams F, Awasthi N, Schwarz MA, Schwarz RE, Li J, von Holzen U. Combination effect of lapatinib with foretinib in HER2 and MET co-activated experimental esophageal adenocarcinoma. Sci Rep. 2019 Nov 26;9(1):17608. doi: 10.1038/s41598-019-54129-7.
Liu, L.; Greger, J.; Shi, H.; Liu, Y.; Greshock, J.; Annan, R.; Halsey, W.; Sathe, G.M.; Martin, A.M.; Gilmer, T.M. Novel mechanism of lapatinib resistance in HER2-positive breast tumor cells: Activation of AXL. Cancer Res. 2009, 69, 6871–6878.
Yau TCC, Lencioni R, Sukeepaisarnjaroen W, Chao Y, Yen CJ, Lausoontornsiri W, Chen PJ, Sanpajit T, Camp A, Cox DS, Gagnon RC, Liu Y, Raffensperger KE, Kulkarni DA, Kallender H, Ottesen LH,
Yang, P.W.; Liu, Y.C.; Chang, Y.H.; Lin, C.C.; Huang, P.M.; Hua, K.T.; Lee, J.M.; Hsieh, M.S. Cabozantinib (XL184) and R428 (BGB324) Inhibit the Growth of Esophageal Squamous Cell Carcinoma (ESCC). Front. Oncol. 2019, 9, 1138.
Choueiri, T.K.; Powles, T.; Burotto, M.; Escudier, B.; Bourlon, M.T.; Zurawski, B.; Oyervides Juarez, V.M.; Hsieh, J.J.; Basso, U.; Shah, A.Y.; et al. Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N. Engl. J. Med. 2021, 384, 829–841.
Diane M. Bodenmiller, Julie A. Stewart, Glenn F. Evans, Victoria L. Peek, Jennifer R. Stephens, Xi Lin, Seema Iyer, Beverly L. Falcon, Sudhakar Chintharlapalli, Sau-Chi Betty Yan, Anthony S. Fischl. Characterization of the anti-angiogenic properties of merestinib (LY2801653), an oncokinase inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1823. doi:10.1158/1538-7445.AM2017-1823
Bruce W. Konicek, Steve M. Bray, Andrew R. Capen, John N. Calley, Kelly M. Credille, Philip J. Ebert, Gary Heady, Bharvin K. Patel, Victoria L. Peek, Jennifer R. Stephens, Suzane L. Um, Melinda D. Willard, Isabella H. Wulur, Yi Zeng, Richard A. Walgren, Sau-Chi Betty Yan. Merestinib (LY2801653), targeting several oncokinases including NTRK1/2/3, shows potent anti-tumor effect in colorectal cell line- and patient-derived xenograft (PDX) model bearing TPM3-NTRK1 fusion. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2647.
Zhu C, Shi H, Wu M, Wei X. A dual MET/AXL small-molecule inhibitor exerts efficacy against gastric carcinoma through killing cancer cells as well as modulating tumor microenvironment. MedComm. 2020; 1: 103–118. https://doi.org/10.1002/mco2.11
Kollmannsberger C, Hurwitz H, Bazhenova L, Cho BC, Hong D, Park K, Reckamp KL, Sharma S, Der-Torossian H, Christensen JG, Faltaos D, Potvin D, Tassell V, Chao R, Shapiro GI. Phase I Study Evaluating Glesatinib (MGCD265), An Inhibitor of MET and AXL, in Patients with Non-small Cell Lung Cancer and Other Advanced Solid Tumors. Target Oncol. 2023 Jan;18(1):105-118. doi: 10.1007/s11523-022-00931-9. Epub 2022 Dec 2.
