Novel mechanism of lapatinib resistance in HER2-positive breast tumor cells: activation of AXL.

HER2-directed therapies, such as trastuzumab and lapatinib, are important treatments for breast cancer. However, some tumors do not respond or develop resistance to these agents. We isolated and characterized multiple lapatinib-resistant, HER2-positive, estrogen receptor (ER)-positive breast cancer clones derived from lapatinib-sensitive BT474 cells by chronic exposure to lapatinib. We show overexpression of AXL as a novel mechanism of acquired resistance to HER2-targeted agents in these models. GSK1363089 (foretinib), a multikinase inhibitor of AXL, MET, and vascular endothelial growth factor receptor currently in phase II clinical trials, restores lapatinib and trastuzumab sensitivity in these resistant cells that exhibit increased AXL expression. Furthermore, small interfering RNA to AXL, estrogen deprivation, or fulvestrant, an ER antagonist, decreases AXL expression and restores sensitivity to lapatinib in these cells. Taken together, these data provide scientific evidence to assess the expression of AXL in HER2-positive, ER-positive patients who have progressed on either lapatinib or trastuzumab and to test the combination of HER2-targeted agents and GSK1363089 in the clinic.

[1]  H. Yamane,et al.  Axl receptor tyrosine kinase stimulated by the vitamin K-dependent protein encoded by growth-arrest-specific gene 6 , 1995, Nature.

[2]  László Orfi,et al.  AXL is a potential target for therapeutic intervention in breast cancer progression. , 2008, Cancer research.

[3]  M. Moasser,et al.  Targeting HER proteins in cancer therapy and the role of the non-target HER3 , 2007, British Journal of Cancer.

[4]  K. Hirokawa,et al.  Overexpression of protein tyrosine kinases in human esophageal cancer. , 1997, Pathobiology : journal of immunopathology, molecular and cellular biology.

[5]  J. Backer,et al.  In brain, Axl recruits Grb2 and the p85 regulatory subunit of PI3 kinase; in vitro mutagenesis defines the requisite binding sites for downstream Akt activation , 2008, Journal of neurochemistry.

[6]  Robert A Copeland,et al.  Characterization of an Akt kinase inhibitor with potent pharmacodynamic and antitumor activity. , 2008, Cancer research.

[7]  H. Varmus,et al.  Acquired Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib Is Associated with a Second Mutation in the EGFR Kinase Domain , 2005, PLoS medicine.

[8]  T. Hunter,et al.  Akt inhibitor A-443654 induces rapid Akt Ser-473 phosphorylation independent of mTORC1 inhibition , 2007, Oncogene.

[9]  E. Liu,et al.  Receptor tyrosine kinases expressed in metastatic colon cancer , 1995, International journal of cancer.

[10]  A. Ullrich,et al.  Axl and Growth Arrest–Specific Gene 6 Are Frequently Overexpressed in Human Gliomas and Predict Poor Prognosis in Patients with Glioblastoma Multiforme , 2008, Clinical Cancer Research.

[11]  S. Yamashita,et al.  Expression of the Axl receptor tyrosine kinase in human thyroid carcinoma. , 1999, Thyroid : official journal of the American Thyroid Association.

[12]  Shinichiro,et al.  Carcinoma , 1906, The Hospital.

[13]  R. Bernards,et al.  PI3 kinase activation and response to trastuzumab or lapatinib in HER-2 overexpressing locally advanced breast cancer (LABC). , 2009 .

[14]  Ming-Tseh Lin,et al.  Receptor tyrosine kinase AXL is induced by chemotherapy drugs and overexpression of AXL confers drug resistance in acute myeloid leukemia. , 2008, Cancer letters.

[15]  H. Allgayer,et al.  The human receptor tyrosine kinase Axl gene--promoter characterization and regulation of constitutive expression by Sp1, Sp3 and CpG methylation. , 2008, Bioscience reports.

[16]  P. Hegde,et al.  A model of acquired autoresistance to a potent ErbB2 tyrosine kinase inhibitor and a therapeutic strategy to prevent its onset in breast cancer , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[17]  T. Fujita,et al.  PTEN activity could be a predictive marker of trastuzumab efficacy in the treatment of ErbB2-overexpressing breast cancer , 2006, British Journal of Cancer.

[18]  N. Hellyer,et al.  ErbB3 (HER3) interaction with the p85 regulatory subunit of phosphoinositide 3-kinase. , 1998, The Biochemical journal.

[19]  A. Martin,et al.  Assessment of epidermal growth factor receptor (EGFR, ErbB1) and HER2 (ErbB2) protein expression levels and response to lapatinib (Tykerb®, GW572016) in an expanded panel of human normal and tumour cell lines , 2007, Cell proliferation.

[20]  H. Garewal,et al.  A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors , 2007, Oncogene.

[21]  B. Dahlbäck,et al.  Signalling and functional diversity within the Axl subfamily of receptor tyrosine kinases. , 2006, Cytokine & growth factor reviews.

[22]  Ron Bose,et al.  Phosphoproteomic analysis of Her2/neu signaling and inhibition. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[23]  H. Gómez,et al.  Lapatinib combined with letrozole vs. letrozole alone for front line postmenopausal hormone receptor positive (HR+) metastatic breast cancer (MBC): first results from the EGF30008 Trial. , 2009 .

[24]  S. Chuang,et al.  Sulfasalazine suppresses drug resistance and invasiveness of lung adenocarcinoma cells expressing AXL. , 2007, Cancer research.

[25]  Ming Tan,et al.  PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. , 2004, Cancer cell.

[26]  M. Dowsett,et al.  Integration of signal transduction inhibitors with endocrine therapy: an approach to overcoming hormone resistance in breast cancer. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[27]  B. Chung,et al.  Expression of the proto-oncogene Axl in renal cell carcinoma. , 2003, DNA and cell biology.

[28]  C. Chi,et al.  Clinical significance of AXL kinase family in gastric cancer. , 2002, Anticancer research.

[29]  R. Espinosa,et al.  axl, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase , 1991, Molecular and cellular biology.

[30]  A. Schulz,et al.  A novel putative tyrosine kinase receptor with oncogenic potential. , 1991, Oncogene.

[31]  T. Tamaya,et al.  Coexpression of Gas6/Axl in Human Ovarian Cancers , 2004, Oncology.

[32]  J. Smyth,et al.  Altered ErbB receptor signaling and gene expression in cisplatin-resistant ovarian cancer. , 2005, Cancer research.

[33]  R. Nahta,et al.  Lapatinib induces apoptosis in trastuzumab-resistant breast cancer cells: effects on insulin-like growth factor I signaling , 2007, Molecular Cancer Therapeutics.

[34]  R. Pazdur,et al.  FDA drug approval summary: lapatinib in combination with capecitabine for previously treated metastatic breast cancer that overexpresses HER-2. , 2008, The oncologist.

[35]  M. Dowsett,et al.  Aromatase inhibitors: Combinations with fulvestrant or signal transduction inhibitors as a strategy to overcome endocrine resistance , 2005, The Journal of Steroid Biochemistry and Molecular Biology.

[36]  Adrian V. Lee,et al.  Estrogen receptor-positive, progesterone receptor-negative breast cancer: association with growth factor receptor expression and tamoxifen resistance. , 2005, Journal of the National Cancer Institute.

[37]  M. Berger,et al.  Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells. , 2006, Cancer research.

[38]  Y. Chu,et al.  Expression of axl in lung adenocarcinoma and correlation with tumor progression. , 2005, Neoplasia.

[39]  E. Dreher,et al.  Estrogen dependent expression of the receptor tyrosine kinase axl in normal and malignant human breast. , 2001, Annals of oncology : official journal of the European Society for Medical Oncology.

[40]  R. Nahta,et al.  Lapatinib induces apoptosis in trastuzumab-resistant breast cancer cells: Effects on insulin-like growth factor I signaling (Molecular Cancer Therapeutics (2007) 6, (667-674)) , 2008 .

[41]  Joon-Oh Park,et al.  MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling , 2007, Science.

[42]  E. Liu,et al.  Determinants for transformation induced by the Axl receptor tyrosine kinase , 1998, Oncogene.