Novel Mechanism of Lapatinib Resistance in HER2-Positive Breast Tumor Cells: Activation of AXL

Abstract

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. [Cancer Res 2009;69(17):6871-8]

LAMC2 enhances the metastatic potential of lung adenocarcinoma

“…The receptor tyrosine kinase AXL is an oncogene shown to promote tumor cell growth, metastasis, and drug resistance to HER2 and epithelial growth factor receptor-targeted therapy. [22][23][24][25] LAMC2 expression has been shown to be associated with prognosis in several solid tumors, 5,9-14 but its role in the metastatic process is not clear.…”

Mechanism of action of the multikinase inhibitor Foretinib

“…It also exerts additional inhibitory activity toward KIT, Flt-3 and the PDGFR. [12][13][14][15] Foretinib inhibits HGF-induced MET phosphorylation and VEGF-induced extracellular signal-regulated kinase phosphorylation and prevents both HGF-induced responses of tumor cells and HGF/VEGF-induced responses of endothelial cells. 16 There are also compelling in vivo evidence that Foretinib may prevent tumor growth through a direct effect on tumor cell proliferation and inhibition of invasion and angiogenesis mediated by HGF and VEGF receptors.…”

“…Recently, Foretinib has been reported to inhibit Axl, a RTK initially identified in CML cells. [12][13][14]16 We recently generated Imatinib-resistant CML cell lines that display increased expression of AXL at the mRNA and protein levels. 8 To investigate the potential role of Axl in the resistance of IM-R cells to Imatinib we used Foretinib in an attempt to inhibit Axlmediated signaling.…”

Identifying Differentially Expressed Genes and Screening Small Molecule Drugs for Lapatinib-resistance of Breast Cancer by a Bioinformatics Strategy

“…Thus, methods related to global gene expression profiling that involved multifactors might help explore the mechanisms Microarray is an effective high-throughput measure for detecting global changes in gene expression and has been widely utilized for exploring concrete mechanisms of pathogenesis. Using this tool, studies described the gene expression profile of acquired Lapatinib-resistant breast cancer cells (Liu et al, 2009). Therefore, to develop drugs with better therapeutic effects, it is important to continue the study of gene expression profile related to acquired Lapatinib-resistance.…”

“…This dataset, deposited by Liu et al in 2009(Liu et al, 2009, contains information about HER2 positive breast cancer cell line BT474 (Lapatinib-sensitive) and BT474-J4 (acquired Lapatinib-resistance cell line). Then, the dataset was analyzed by dChip software (v.2011.01) (http: //www.…”