Mechanisms of AXL Overexpression and Function in Imatinib-resistant Chronic Myeloid Leukemia Cells

Overview

Journal Oncotarget

Specialty Oncology

Date 2011 Dec 6

PMID 22141136

Citations 56

Authors

Maeva Dufies

Arnaud Jacquel

Nathalie Belhacene

Guillaume Robert

Thomas Cluzeau

Frederic Luciano

Jill Patrice Cassuto

Sophie Raynaud

Patrick Auberger

Affiliations

Soon will be listed here.

Abstract

AXL is a receptor tyrosine kinase of the TAM family, the function of which is poorly understood. We previously identified AXL overexpression in Imatinib (IM)-resistant CML cell lines and patients. The present study was conducted to investigate the role of AXL and the mechanisms underlying AXL overexpression in Tyrosine Kinase Inhibitor (TKI)-resistant CML cells. We present evidence that high AXL expression level is a feature of TKI-resistant CML cells and knockdown of AXL sensitized TKI-resistant cells to IM. In addition, expression of wild-type AXL but not a dominant negative form of AXL confers IM-sensitive CML cells the capacity to resist IM effect. AXL overexpression required PKCα and β and constitutive activation of ERK1/2. Accordingly, GF109203X a PKC inhibitor, U0126 a MEK1 inhibitor and PKCα/β knockdown restore sensitivity to IM while PKCα or PKCβ overexpression in CML cells promotes protection against IM-induced cell death. Finally, using luciferase promoter activity assays we established that AXL is regulated transcriptionally through the AP1 transcription factor. Our findings reveal an unexpected role of AXL in resistance to TKI in CML cells, identify the molecular mechanisms involved in its overexpression and support the notion that AXL is a new marker of resistance to TKI in CML.

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References

Maulon L, Mari B, Bertolotto C, Ricci J, Luciano F, Belhacene N . Differential requirements for ERK1/2 and P38 MAPK activation by thrombin in T cells. Role of P59Fyn and PKCepsilon. Oncogene. 2001; 20(16):1964-72. DOI: 10.1038/sj.onc.1204266. View

Ghosh A, Secreto C, Boysen J, Sassoon T, Shanafelt T, Mukhopadhyay D . The novel receptor tyrosine kinase Axl is constitutively active in B-cell chronic lymphocytic leukemia and acts as a docking site of nonreceptor kinases: implications for therapy. Blood. 2010; 117(6):1928-37. PMC: 3056640. DOI: 10.1182/blood-2010-09-305649. View

Li Y, Ye X, Tan C, Hongo J, Zha J, Liu J . Axl as a potential therapeutic target in cancer: role of Axl in tumor growth, metastasis and angiogenesis. Oncogene. 2009; 28(39):3442-55. DOI: 10.1038/onc.2009.212. View

Welsh J, Mahadevan D, Ellsworth R, Cooke L, Bearss D, Stea B . The c-Met receptor tyrosine kinase inhibitor MP470 radiosensitizes glioblastoma cells. Radiat Oncol. 2009; 4:69. PMC: 2806296. DOI: 10.1186/1748-717X-4-69. View

Fang G, Kim C, PERKINS C, Ramadevi N, Winton E, Wittmann S . CGP57148B (STI-571) induces differentiation and apoptosis and sensitizes Bcr-Abl-positive human leukemia cells to apoptosis due to antileukemic drugs. Blood. 2000; 96(6):2246-53. View

Gamas P, Marchetti S, Puissant A, Grosso S, Jacquel A, Colosetti P . Inhibition of imatinib-mediated apoptosis by the caspase-cleaved form of the tyrosine kinase Lyn in chronic myelogenous leukemia cells. Leukemia. 2009; 23(8):1500-6. DOI: 10.1038/leu.2009.60. View

Limb J, Yoon S, Lee K, Kim B, Lee S, Bae Y . Regulation of megakaryocytic differentiation of K562 cells by FosB, a member of the Fos family of AP-1 transcription factors. Cell Mol Life Sci. 2009; 66(11-12):1962-73. PMC: 11115838. DOI: 10.1007/s00018-009-8775-5. View

Hafizi S, Dahlback B . Signalling and functional diversity within the Axl subfamily of receptor tyrosine kinases. Cytokine Growth Factor Rev. 2006; 17(4):295-304. DOI: 10.1016/j.cytogfr.2006.04.004. View

Fridell Y, Jin Y, Quilliam L, Burchert A, MCCLOSKEY P, Spizz G . Differential activation of the Ras/extracellular-signal-regulated protein kinase pathway is responsible for the biological consequences induced by the Axl receptor tyrosine kinase. Mol Cell Biol. 1996; 16(1):135-45. PMC: 230987. DOI: 10.1128/MCB.16.1.135. View

10.

Macleod K, Mullen P, Sewell J, Rabiasz G, Lawrie S, Miller E . Altered ErbB receptor signaling and gene expression in cisplatin-resistant ovarian cancer. Cancer Res. 2005; 65(15):6789-800. DOI: 10.1158/0008-5472.CAN-04-2684. View

11.

Mahadevan D, Cooke L, Riley C, Swart R, Simons B, Della Croce K . A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors. Oncogene. 2007; 26(27):3909-19. DOI: 10.1038/sj.onc.1210173. View

12.

Hong C, Lay J, Huang J, Cheng A, Tang J, Lin M . Receptor tyrosine kinase AXL is induced by chemotherapy drugs and overexpression of AXL confers drug resistance in acute myeloid leukemia. Cancer Lett. 2008; 268(2):314-24. DOI: 10.1016/j.canlet.2008.04.017. View

13.

Huang F, Hurlburt W, Greer A, Reeves K, Hillerman S, Chang H . Differential mechanisms of acquired resistance to insulin-like growth factor-i receptor antibody therapy or to a small-molecule inhibitor, BMS-754807, in a human rhabdomyosarcoma model. Cancer Res. 2010; 70(18):7221-31. DOI: 10.1158/0008-5472.CAN-10-0391. View

14.

Linger R, Keating A, Earp H, Graham D . TAM receptor tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer. Adv Cancer Res. 2008; 100:35-83. PMC: 3133732. DOI: 10.1016/S0065-230X(08)00002-X. View

15.

Vajkoczy P, Knyazev P, Kunkel A, Capelle H, Behrndt S, von Tengg-Kobligk H . Dominant-negative inhibition of the Axl receptor tyrosine kinase suppresses brain tumor cell growth and invasion and prolongs survival. Proc Natl Acad Sci U S A. 2006; 103(15):5799-804. PMC: 1458653. DOI: 10.1073/pnas.0510923103. View

16.

Dan S, Naito M, Tsuruo T . Selective induction of apoptosis in Philadelphia chromosome-positive chronic myelogenous leukemia cells by an inhibitor of BCR - ABL tyrosine kinase, CGP 57148. Cell Death Differ. 1999; 5(8):710-5. DOI: 10.1038/sj.cdd.4400400. View

17.

Verma A, Warner S, Vankayalapati H, Bearss D, Sharma S . Targeting Axl and Mer kinases in cancer. Mol Cancer Ther. 2011; 10(10):1763-73. DOI: 10.1158/1535-7163.MCT-11-0116. View

18.

Mahon F, Deininger M, Schultheis B, Chabrol J, Reiffers J, Goldman J . Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. Blood. 2000; 96(3):1070-9. View

19.

Liu L, Greger J, Shi H, Liu Y, Greshock J, Annan R . Novel mechanism of lapatinib resistance in HER2-positive breast tumor cells: activation of AXL. Cancer Res. 2009; 69(17):6871-8. DOI: 10.1158/0008-5472.CAN-08-4490. View

20.

Robert G, Sahra I, Puissant A, Colosetti P, Belhacene N, Gounon P . Acadesine kills chronic myelogenous leukemia (CML) cells through PKC-dependent induction of autophagic cell death. PLoS One. 2009; 4(11):e7889. PMC: 2775681. DOI: 10.1371/journal.pone.0007889. View