Activation of the AXL Kinase Causes Resistance to EGFR-Targeted Therapy in Lung Cancer

Article (PDF Available)inNature Genetics 44(8):852-60 · July 2012with162 Reads
DOI: 10.1038/ng.2330 · Source: PubMed
Human non-small cell lung cancers (NSCLCs) with activating mutations in EGFR frequently respond to treatment with EGFR-targeted tyrosine kinase inhibitors (TKIs), such as erlotinib, but responses are not durable, as tumors acquire resistance. Secondary mutations in EGFR (such as T790M) or upregulation of the MET kinase are found in over 50% of resistant tumors. Here, we report increased activation of AXL and evidence for epithelial-to-mesenchymal transition (EMT) in multiple in vitro and in vivo EGFR-mutant lung cancer models with acquired resistance to erlotinib in the absence of the EGFR p.Thr790Met alteration or MET activation. Genetic or pharmacological inhibition of AXL restored sensitivity to erlotinib in these tumor models. Increased expression of AXL and, in some cases, of its ligand GAS6 was found in EGFR-mutant lung cancers obtained from individuals with acquired resistance to TKIs. These data identify AXL as a promising therapeutic target whose inhibition could prevent or overcome acquired resistance to EGFR TKIs in individuals with EGFR-mutant lung cancer.

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Available from: Dae Ho Lee
    • "However, the drug responses are not durable due to the acquired resistance. The secondary mutation in EGFR exon 20 (T790M) was found in approximately 50% of resistant tumors (Zhang et al., 2012; Kumarakulasinghe et al., 2015). Besides the mutation, activation of alternative tyrosine kinase receptors (TKRs) sharing similar downstream pathways with EGFR has been proved to be one of the multiple resistance mechanisms, including c-MET (hepatocyte growth factor receptor), Ron (a protein tyrosine kinase related to c- MET), PDGFR (platelet-derived growth factor receptor), and IGF-1R (insulin-like growth factor receptor-1) (Camp et al., 2005). "
    [Show abstract] [Hide abstract] ABSTRACT: Lung cancer is the top cancer killer worldwide with high mortality rate. Majority belong to non-small cell lung cancers (NSCLCs). The epidermal growth factor receptor (EGFR) has been broadly explored as a drug target for therapy. However, the drug responses are not durable due to the acquired resistance. MicroRNAs (miRNAs) are small non-coding and endogenous molecules that can inhibit mRNA translation initiation and degrade mRNAs. We wonder if some downstream molecules shared by EGFR and the other tyrosine kinase receptors (TKRs) further transduce the signals alternatively, and some miRNAs play the key roles in affecting the expression of these downstream molecules. In this study, we investigated the mRNA:miRNA associations for the direct EGFR downstream molecules in the EGFR signaling pathway shared with the other TKRs, including c-MET (hepatocyte growth factor receptor), Ron (a protein tyrosine kinase related to c-MET), PDGFR (platelet-derived growth factor receptor), and IGF-1R (insulin-like growth factor receptor-1). The multiple linear regression and support vector regression (SVR) models were used to discover the statistically significant and the best weighted miRNAs regulating the mRNAs of these downstream molecules. These two models revealed the similar mRNA:miRNA associations. It was found that the miRNAs significantly affecting the mRNA expressions in the multiple regression model were also those with the largest weights in the SVR model. To conclude, we effectively identified a list of meaningful mRNA:miRNA associations: phospholipase C, gamma 1 (PLCG1) with miR-34a, phosphoinositide-3-kinase, regulatory subunit 2 (PIK3R2) with miR-30a-5p, growth factor receptor-bound protein 2 (GRB2) with miR-27a, and Janus kinase 1 (JAK1) with miR-302b and miR-520e. These associations could make great contributions to explore new mechanism in NSCLCs. These candidate miRNAs may be regarded as the potential drug targets for treating NSCLCs with acquired drug resistance.
    Article · Oct 2016
    • "The mNSCLC cell lines HCC827 and HCC827 ER3 are derived from lung adenocarcinoma and have an acquired mutation in the epidermal growth factor receptor (EGFR) tyrosine kinase domain (E746-A750 deletion) [11,12] . HCC827 ER3, in comparison with the parental cell line, is an erlotinib (EGFR tyrosine kinase inhibitor) resistant cell line [13] , but they both contain the heterozygous EGFR exon 19 deletion . The mNSCLC cell lines were generously provided by Dr. Trever G. Bivona at University of California, San Francisco (UCSF). "
    [Show abstract] [Hide abstract] ABSTRACT: Improvements in technologies to yield purer circulating tumor cells (CTCs) will enable a broader range of clinical applications. We have previously demonstrated the use of a commercially available cell-adhesion matrix (CAM) assay to capture invasive CTCs (iCTCs). To improve the purity of the isolated iCTCs, here we used fluorescence-activated cell sorting (FACS) in combination with the CAM assay (CAM + FACS). Our results showed an increase of median purity from the CAM assay to CAM + FACS for the spiked-in cell lines and patient samples analyzed from three different metastatic cancer types: castration resistant prostate cancer (mCRPC), non-small cell lung cancer (mNSCLC) and pancreatic ductal adenocarcinoma cancer (mPDAC). Copy number profiles for spiked-in mCRPC cell line and mCRPC patient iCTCs were similar to expected mCRPC profiles and a matched biopsy. A somatic epidermal growth factor receptor (EGFR) mutation specific to mNSCLC was observed in the iCTCs recovered from EGFR+ mNSCLC cell lines and patient samples. Next-generation sequencing (NGS) of spiked-in pancreatic cancer cell line and mPDAC patient iCTCs showed mPDAC common mutations. CAM + FACS iCTC enrichment enables multiple downstream genomic characterizations across different tumor types.
    Full-text · Article · Jun 2016
    • "Because tumors with stem-like features have been shown to lead to poor survival and resistance to therapies, AXL strong expression in our lung cancer patients may promote such features and contribute to their poorer prognosis. AXL activation has been recently reported to confer acquired resistance to EGFR-TKIs in lung cancers with EGFR mutations [12, 31, 32]. However a patient in this study, whose LAD specimen had 3+ AXL expression and an EGFR mutation, responded well to gefitinib. "
    [Show abstract] [Hide abstract] ABSTRACT: The receptor tyrosine kinase AXL is a member of the Tyro3-Axl-Mer receptor tyrosine kinase subfamily. AXL affects several cellular functions, including growth and migration. AXL aberration is reportedly a marker for poor prognosis and treatment resistance in various cancers. In this study, we analyzed clinical, pathological, and molecular features of AXL expression in lung adenocarcinomas (LADs). We examined 161 LAD specimens from patients who underwent pulmonary resections. When AXL protein expression was quantified (0, 1+, 2+, 3+) according to immunohistochemical staining intensity, results were 0: 35%; 1+: 20%; 2+: 37%; and 3+: 7% for the 161 samples. AXL expression status did not correlate with clinical features, including smoking status and pathological stage. However, patients whose specimens showed strong AXL expression (3+) had markedly poorer prognoses than other groups (P = 0.0033). Strong AXL expression was also significantly associated with downregulation of E-cadherin (P = 0.025) and CD44 (P = 0.0010). In addition, 9 of 12 specimens with strong AXL expression had driver gene mutations (6 with EGFR, 2 with KRAS, 1 with ALK). In conclusion, we found that strong AXL expression in surgically resected LADs was a predictor of poor prognosis. LADs with strong AXL expression were characterized by mesenchymal status, higher expression of stem-cell-like markers, and frequent driver gene mutations.
    Full-text · Article · Apr 2016
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