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image of Emerging AXL Inhibitors in Oncology: Chemical and Biological Advances in 
Targeted Cancer Therapy

Abstract

AXL, a receptor tyrosine kinase, has emerged as a critical player in tumorigenesis, metastasis, and resistance to conventional therapies. Its aberrant activation drives cell proliferation, survival, and angiogenesis, making it an attractive target for cancer treatment. In recent years, significant progress has been made in the development of AXL inhibitors. Chemical approaches have led to the discovery of small molecules that selectively bind to and inhibit AXL, disrupting its downstream signaling pathways. These inhibitors exhibit diverse structural features, including ATP-competitive and allosteric binding modes, offering potential advantages in terms of selectivity and potency. In addition to chemical approaches, biological strategies have also been explored to target AXL. These include the use of monoclonal antibodies, which can neutralize AXL ligands or induce receptor internalization and degradation. Furthermore, gene therapy techniques have been investigated to downregulate AXL expression or disrupt its signaling pathways. Despite these advancements, challenges remain in the development of AXL inhibitors. Selectivity is a critical concern, as AXL shares homology with other receptor tyrosine kinases. Drug resistance is another obstacle, as cancer cells can develop mechanisms to evade AXL inhibition. Furthermore, to address these challenges, combination therapies are being explored, such as combining AXL inhibitors with other targeted agents or conventional treatments. In conclusion, developing AXL inhibitors represents a promising avenue for improving cancer treatment outcomes. Continued research efforts are essential to overcome the existing challenges and translate these compounds into effective clinical therapies.

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2024-12-13
2025-01-18

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References

  1. Jänne P.A. Yang J.C.H. Kim D.W. Planchard D. Ohe Y. Ramalingam S.S. Ahn M.J. Kim S.W. Su W.C. Horn L. Haggstrom D. Felip E. Kim J.H. Frewer P. Cantarini M. Brown K.H. Dickinson P.A. Ghiorghiu S. Ranson M. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N. Engl. J. Med. 2015 372 18 1689 1699 10.1056/NEJMoa1411817 25923549
    [Google Scholar]
  2. Subbiah V. Meyer C. Zinner R. Meric-Bernstam F. Zahurak M.L. O’Connor A. Roszik J. Shaw K. Ludwig J.A. Kurzrock R. Azad N.A. Phase Ib/II study of the safety and efficacy of combination therapy with multikinase VEGF inhibitor pazopanib and mek inhibitor trametinib in advanced soft tissue sarcoma. Clin. Cancer Res. 2017 23 15 4027 4034 10.1158/1078‑0432.CCR‑17‑0272 28377484
    [Google Scholar]
  3. Gay C.M. Balaji K. Byers L.A. Giving AXL the axe: Targeting AXL in human malignancy. Br. J. Cancer 2017 116 4 415 423 10.1038/bjc.2016.428 28072762
    [Google Scholar]
  4. Feneyrolles C. Spenlinhauer A. Guiet L. Fauvel B. Daydé-Cazals B. Warnault P. Chevé G. Yasri A. Axl kinase as a key target for oncology: Focus on small molecule inhibitors. Mol. Cancer Ther. 2014 13 9 2141 2148 10.1158/1535‑7163.MCT‑13‑1083 25139999
    [Google Scholar]
  5. Barata P.C. Rini B.I. Treatment of renal cell carcinoma: Current status and future directions. CA Cancer J. Clin. 2017 67 6 507 524 10.3322/caac.21411 28961310
    [Google Scholar]
  6. Liu E. Hjelle B. Bishop J.M. Transforming genes in chronic myelogenous leukemia. Proc. Natl. Acad. Sci. USA 1988 85 6 1952 1956 10.1073/pnas.85.6.1952 3279421
    [Google Scholar]
  7. Graham D.K. DeRyckere D. Davies K.D. Earp H.S. The TAM family: Phosphatidylserine-sensing receptor tyrosine kinases gone awry in cancer. Nat. Rev. Cancer 2014 14 12 769 785 10.1038/nrc3847 25568918
    [Google Scholar]
  8. Groffen J. Stephenson J. Heisterkamp N. Deklein A. Bartram C. Grosveld G. Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell 1984 36 1 93 99 10.1016/0092‑8674(84)90077‑1 6319012
    [Google Scholar]
  9. Deininger M.W.N. Goldman J.M. Melo J.V. The molecular biology of chronic myeloid leukemia. Blood 2000 96 10 3343 3356 10.1182/blood.V96.10.3343
    [Google Scholar]
  10. Steelman L.S. Pohnert S.C. Shelton J.G. JAK/STAT, Raf/MEK/ ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukaemia 2004 18 189 218 10.1038/sj.leu.2403241
    [Google Scholar]
  11. Bosurgi L. Bernink J.H. Delgado Cuevas V. Gagliani N. Joannas L. Schmid E.T. Booth C.J. Ghosh S. Rothlin C.V. Paradoxical role of the proto-oncogene Axl and Mer receptor tyrosine kinases in colon cancer. Proc. Natl. Acad. Sci. USA 2013 110 32 13091 13096 10.1073/pnas.1302507110 23878224
    [Google Scholar]
  12. Schmidt T. Ben-Batalla I. Schultze A. Loges S. Macrophage–tumor crosstalk: role of TAMR tyrosine kinase receptors and of their ligands. Cell. Mol. Life Sci. 2012 69 9 1391 1414 10.1007/s00018‑011‑0863‑7 22076650
    [Google Scholar]
  13. McDermott U. Settleman J. Personalized cancer therapy with selective kinase inhibitors: an emerging paradigm in medical oncology. J. Clin. Oncol. 2009 27 33 5650 5659 10.1200/JCO.2009.22.9054 19858389
    [Google Scholar]
  14. Carragher N.O. Unciti-Broceta A. Cameron D.A. Advancing cancer drug discovery towards more agile development of targeted combination therapies. Future Med. Chem. 2012 4 1 87 105 10.4155/fmc.11.169 22168166
    [Google Scholar]
  15. Holohan C. Van Schaeybroeck S. Longley D.B. Johnston P.G. Cancer drug resistance: an evolving paradigm. Nat. Rev. Cancer 2013 13 10 714 726 10.1038/nrc3599 24060863
    [Google Scholar]
  16. Rosell R. Teixidó C. Huang A. AXL mediates resistance toPI3Kα inhibition by activating the EGFR/PKC/mTOR axis in head and neck and oesophageal squamous cell carcinomas. Cancer Cell 2015 27 533 546 10.1016/j.ccell.2015.03.010
    [Google Scholar]
  17. Sherwood L.M. Parris E.E. Folkman J. Tumor angiogenesis: Therapeutic implications. N. Engl. J. Med. 1971 285 21 1182 1186 10.1056/NEJM197111182852108 4938153
    [Google Scholar]
  18. Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst. 1990 82 1 4 6 10.1016/S0065‑230X(00)79001‑4 10818676
    [Google Scholar]
  19. Cherrington J.M. Strawn L.M. Shawver L.K. New paradigms for the treatment of cancer: The role of anti-angiogenesis agents. Adv. Cancer Res. 2000 79 1 38 10.1016/S0065‑230X(00)79001‑4 10818676
    [Google Scholar]
  20. Hanahan D. Weinberg R.A. The hallmarks of cancer. Cell 2000 100 1 57 70 10.1016/S0092‑8674(00)81683‑9 10647931
    [Google Scholar]
  21. Faivre S. Djelloul S. Raymond E. New paradigms in anticancer therapy: targeting multiple signaling pathways with kinase inhibitors. Semin. Oncol. 2006 33 4 407 420 10.1053/j.seminoncol.2006.04.005 16890796
    [Google Scholar]
  22. Kris M.G. Natale R.B. Herbst R.S. Lynch T.J. Jr Prager D. Belani C.P. Schiller J.H. Kelly K. Spiridonidis H. Sandler A. Albain K.S. Cella D. Wolf M.K. Averbuch S.D. Ochs J.J. Kay A.C. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 2003 290 16 2149 2158 10.1001/jama.290.16.2149 14570950
    [Google Scholar]
  23. Pérez-Soler R. Phase II clinical trial data with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib (OSI-774) in non-small-cell lung cancer. Clin. Lung Cancer 2004 6 Suppl. 1 S20 S23 10.3816/CLC.2004.s.010 15638953
    [Google Scholar]
  24. Paez J.G. Jänne P.A. Lee J.C. Tracy S. Greulich H. Gabriel S. Herman P. Kaye F.J. Lindeman N. Boggon T.J. Naoki K. Sasaki H. Fujii Y. Eck M.J. Sellers W.R. Johnson B.E. Meyerson M. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004 304 5676 1497 1500 10.1126/science.1099314 15118125
    [Google Scholar]
  25. Sharma S.V. Bell D.W. Settleman J. Haber D.A. Epidermal growth factor receptor mutations in lung cancer. Nat. Rev. Cancer 2007 7 3 169 181 10.1038/nrc2088 17318210
    [Google Scholar]
  26. Sharma S.V. Gajowniczek P. Way I.P. Lee D.Y. Jiang J. Yuza Y. Classon M. Haber D.A. Settleman J. A common signaling cascade may underlie “addiction” to the Src, BCR-ABL, and EGF receptor oncogenes. Cancer Cell 2006 10 5 425 435 10.1016/j.ccr.2006.09.014 17097564
    [Google Scholar]
  27. International Agency for Research on Cancer. GLOBOCAN: kidney cancer estimated. Available from:https://gco.iarc.who.int/en (accessed on 18-11-2024).
  28. Gupta K. Miller J.D. Li J.Z. Russell M.W. Charbonneau C. Epidemiologic and socioeconomic burden of metastatic renal cell carcinoma (mRCC): A literature review. Cancer Treat. Rev. 2008 34 3 193 205 10.1016/j.ctrv.2007.12.001 18313224
    [Google Scholar]
  29. Janzen N.K. Kim H.L. Figlin R.A. Belldegrun A.S. Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease. Urol. Clin. North Am. 2003 30 4 843 852 10.1016/S0094‑0143(03)00056‑9 14680319
    [Google Scholar]
  30. Kroeger N. Choueiri T.K. Lee J.L. Bjarnason G.A. Knox J.J. MacKenzie M.J. Wood L. Srinivas S. Vaishamayan U.N. Rha S.Y. Pal S.K. Yuasa T. Donskov F. Agarwal N. Tan M.H. Bamias A. Kollmannsberger C.K. North S.A. Rini B.I. Heng D.Y.C. Survival outcome and treatment response of patients with late relapse from renal cell carcinoma in the era of targeted therapy. Eur. Urol. 2014 65 6 1086 1092 10.1016/j.eururo.2013.07.031 23916693
    [Google Scholar]
  31. Leibovich B.C. Blute M.L. Cheville J.C. Lohse C.M. Frank I. Kwon E.D. Weaver A.L. Parker A.S. Zincke H. Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma. Cancer 2003 97 7 1663 1671 10.1002/cncr.11234 12655523
    [Google Scholar]
  32. Bernabé R. Patrao A. Carter L. Blackhall F. Dean E. Selumetinib in the treatment of non-small-cell lung cancer. Future Oncol. 2016 12 22 2545 2560 10.2217/fon‑2016‑0132 27467210
    [Google Scholar]
  33. Heigener D.F. Gandara D.R. Reck M. Targeting of MEK in lung cancer therapeutics. Lancet Respir. Med. 2015 3 4 319 327 10.1016/S2213‑2600(15)00026‑0 25801412
    [Google Scholar]
  34. Vilmar A.C. Santoni-Rugiu E. Sørensen J.B. Class III β-tubulin in advanced NSCLC of adenocarcinoma subtype predicts superior outcome in a randomized trial. Clin. Cancer Res. 2011 17 15 5205 5214 10.1158/1078‑0432.CCR‑11‑0658 21690572
    [Google Scholar]
  35. Morgensztern D. Campo M.J. Dahlberg S.E. Doebele R.C. Garon E. Gerber D.E. Goldberg S.B. Hammerman P.S. Heist R.S. Hensing T. Horn L. Ramalingam S.S. Rudin C.M. Salgia R. Sequist L.V. Shaw A.T. Simon G.R. Somaiah N. Spigel D.R. Wrangle J. Johnson D. Herbst R.S. Bunn P. Govindan R. Molecularly targeted therapies in non-small-cell lung cancer annual update 2014. J. Thorac. Oncol. 2015 10 S1 S1 S63 10.1097/JTO.0000000000000405 25535693
    [Google Scholar]
  36. Roberts P.J. Der C.J. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 2007 26 22 3291 3310 10.1038/sj.onc.1210422 17496923
    [Google Scholar]
  37. Liu Y. Yang Y. Ye Y.C. Shi Q.F. Chai K. Tashiro S. Onodera S. Ikejima T. Activation of ERK-p53 and ERK-mediated phosphorylation of Bcl-2 are involved in autophagic cell death induced by the c-Met inhibitor SU11274 in human lung cancer A549 cells. J. Pharmacol. Sci. 2012 118 4 423 432 10.1254/jphs.11181FP 22466960
    [Google Scholar]
  38. Chiba M. Togashi Y. Tomida S. Mizuuchi H. Nakamura Y. Banno E. Hayashi H. Terashima M. De Velasco M.A. Sakai K. Fujita Y. Mitsudomi T. Nishio K. MEK inhibitors against MET-amplified non-small cell lung cancer. Int. J. Oncol. 2016 49 6 2236 2244 10.3892/ijo.2016.3736 27748834
    [Google Scholar]
  39. Waters A.M. Khatib T.O. Papke B. Goodwin C.M. Hobbs G.A. Diehl J.N. Yang R. Edwards A.C. Walsh K.H. Sulahian R. McFarland J.M. Kapner K.S. Gilbert T.S.K. Stalnecker C.A. Javaid S. Barkovskaya A. Grover K.R. Hibshman P.S. Blake D.R. Schaefer A. Nowak K.M. Klomp J.E. Hayes T.K. Kassner M. Tang N. Tanaseichuk O. Chen K. Zhou Y. Kalkat M. Herring L.E. Graves L.M. Penn L.Z. Yin H.H. Aguirre A.J. Hahn W.C. Cox A.D. Der C.J. Targeting p130Cas- and microtubule-dependent MYC regulation sensitizes pancreatic cancer to ERK MAPK inhibition. Cell Rep. 2021 35 13 109291 10.1016/j.celrep.2021.109291 34192548
    [Google Scholar]
  40. Heinrich M.C. Corless C.L. Duensing A. McGreevey L. Chen C.J. Joseph N. Singer S. Griffith D.J. Haley A. Town A. Demetri G.D. Fletcher C.D.M. Fletcher J.A. PDGFRA activating mutations in gastrointestinal stromal tumors. Science 2003 299 5607 708 710 10.1126/science.1079666 12522257
    [Google Scholar]
  41. Corless C.L. McGreevey L. Haley A. Town A. Heinrich M.C. KIT mutations are common in incidental gastrointestinal stromal tumors one centimeter or less in size. Am. J. Pathol. 2002 160 5 1567 1572 10.1016/S0002‑9440(10)61103‑0 12000708
    [Google Scholar]
  42. Qiao G.B. Wu Y.L. Yang X.N. Zhong W.Z. Xie D. Guan X.Y. Fischer D. Kolberg H.C. Kruger S. Stuerzbecher H-W. High-level expression of Rad51 is an independent prognostic marker of survival in non-small-cell lung cancer patients. Br. J. Cancer 2005 93 1 137 143 10.1038/sj.bjc.6602665 15956972
    [Google Scholar]
  43. Hansen L.T. Lundin C. Spang-Thomsen M. Petersen L.N. Helleday T. The role of RAD51 in etoposide (VP16) resistance in small cell lung cancer. Int. J. Cancer 2003 105 4 472 479 10.1002/ijc.11106 12712436
    [Google Scholar]
  44. Henning W. Stürzbecher H.W. Homologous recombination and cell cycle checkpoints: Rad51 in tumour progression and therapy resistance. Toxicology 2003 193 1-2 91 109 10.1016/S0300‑483X(03)00291‑9 14599770
    [Google Scholar]
  45. ICH harmonised tripartite guideline nonclinical evaluation for anticancer pharmaceuticals. 2009 Available from:https://database.ich.org/sites/default/files/S9_Guideline.pdf (accessed on 18-11-2024).
/content/journals/acamc/10.2174/0118715206351185241209053053
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Emerging AXL Inhibitors in Oncology: Chemical and Biological Advances in 
Targeted Cancer Therapy
Bentham Science Publishers ; https://doi.org/10.2174/0118715206351185241209053053
/content/journals/acamc/10.2174/0118715206351185241209053053
/content/journals/acamc/10.2174/0118715206351185241209053053
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  • Article Type:     Review Article
Keywords: cabozantinib ; amuvatinib ; AXL inhibitors ; MGCD265 ; foretinib

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