Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer

Zhang, Zhenfeng; Lee, Jae Cheol; Li, Lin; Olivas, Victor; Au, Valerie; LaFramboise, Thomas; Abdel-Rahman, Mohamed; Wang, Xiaoqi; Levine, Alan D.; Rho, Jin Kyung; Choi, Yun Jung; Choi, Chang; Kim, Sang We; Jang, Se Jin; Park, Young Soo; Kim, Woo Sung; Lee, Dong Hoon; Lee, Jung Shin; Miller, Vincent A.; Arcila, Maria E.; Ladanyi, Marc; Moonsamy, Philicia; Sawyers, Charles L.; Boggon, Titus J.; Patrick, C.; Costa, Carlota; Tarón, Miquel; Rosell, Rafael; Halmos, Balázs; Bivona, Trever G.

doi:10.1038/ng.2330

Cited by 1,032 publications

(1,121 citation statements)

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“…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.…”

Section: Resultsmentioning

confidence: 99%

LAMC2 enhances the metastatic potential of lung adenocarcinoma

et al. 2015

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Lung cancer is the number one cancer killer, and metastasis is the main cause of high mortality in lung cancer patients. However, mechanisms underlying the development of lung cancer metastasis remain unknown. Using genome-wide transcriptional analysis in an experimental metastasis model, we identified laminin γ2 (LAMC2), an epithelial basement membrane protein, to be significantly upregulated in lung adenocarcinoma metastatic cells. Elevated LAMC2 increased traction force, migration, and invasion of lung adenocarcinoma cells accompanied by the induction of epithelial-mesenchymal transition (EMT). LAMC2 knockdown decreased traction force, migration, and invasion accompanied by EMT reduction in vitro, and attenuated metastasis in mice. LAMC2 promoted migration and invasion via EMT that was integrin β1-and ZEB1-dependent. High LAMC2 was significantly correlated with the mesenchymal marker vimentin expression in lung adenocarcinomas, and with higher risk of recurrence or death in patients with lung adenocarcinoma. We suggest that LAMC2 promotes metastasis in lung adenocarcinoma via EMT and may be a potential therapeutic target. Cell Death and Differentiation (2015) 22, 1341-1352; doi:10.1038/cdd.2014.228; published online 16 January 2015Lung cancer is the leading cause of cancer-related death. 1 Non-small-cell lung cancer (NSCLC) accounts for~80-85% of lung cancers. 2 Only 20-30% of NSCLC are radically resectable and the majority of lung cancer patients succumb to the disease. The high mortality of NSCLC is largely attributable to late diagnosis, when metastases are present. 2 The molecular mechanisms governing metastasis of NSCLC remain poorly understood.Metastasis is a complex, multistep process, involving migration and invasion of malignant cells from the primary tumor to blood vessels, intravasation, and survival in the circulation, and ultimately extravasation, colonization, and formation of secondary tumor at distant target organs. 3 Each of these events is classically driven by the acquisition of genetic and/or epigenetic traits in tumor cells and the cooperation of nonneoplastic stromal cells. Increased or decreased expression of several genes in tumors has been found to be correlated with metastasis. 3 However, specific gene alterations that drive NSCLC metastasis remain largely elusive.Laminin γ2 (LAMC2) is a subunit of the heterotrimeric glycoprotein laminin-332 (LAM-332, formerly laminin-5), consisting of the α3, β3, and γ2 chains. Although LAMC2 is an important structural component of the epithelial basement membrane (BM) in various normal tissues, 4 there is an emerging evidence for a pathological role of LAMC2 monomer in cancer. It has been demonstrated that LAMC2 protein expression correlates with clinical outcome of stage I lung adenocarcinoma (ADC) patients. 5,6 In addition, noncontinuous expression pattern of LAMC2 predicts the prognosis of esophageal squamous cell carcinoma (SCC), 7 and secreted LAMC2 in the serum is associated with the aggressiveness of pancreatic cancer. 8 Besides, LAMC2 monom...

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Section: Resultsmentioning

confidence: 99%

LAMC2 enhances the metastatic potential of lung adenocarcinoma

et al. 2015

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“…9 In HCC827 GR2 cells, AXL kinase expression was too low for detection by western blotting, and although HCC4006 GR3 cells clearly expressed AXL, they did not require the kinase for survival. In addition, while some reports show that aberrant Met activation via mutation or ligand activity secreted by stromal cells induces EMT and promotes invasion of carcinoma cells in many types of cancers, [35][36][37] the GR cells characterized in this study did not depend on Met signaling for survival.…”

Section: Discussionmentioning

confidence: 99%

“…4 EGFR-mutated tumors can also acquire resistance to EGFR TKIs through epithelial-tomesenchymal transition (EMT). [5][6][7][8] Furthermore, the AXL receptor tyrosine kinase has been shown to have a key role in EMT-induced drug resistance; 9 however, it remains unclear whether AXL activation invariably occurs in EGFR-mutant carcinoma cells showing an EMT phenotype.…”

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confidence: 99%

Enhanced autophagy is required for survival in EGFR-independent EGFR-mutant lung adenocarcinoma cells

Sakuma

Matsukuma

Nakamura

et al. 2013

Laboratory Investigation

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Lung cancers harboring epidermal growth factor receptor (EGFR) mutations depend on constitutive activation of the kinase for survival. Although most EGFR-mutant lung cancers are sensitive to EGFR tyrosine kinase inhibitors (TKIs) and shrink in response to treatment, acquired resistance to TKI therapy is common. We demonstrate here that two EGFRmutated lung adenocarcinoma cell lines, HCC827 and HCC4006, contain a subpopulation of cells that have undergone epithelial-to-mesenchymal transition and survive independent of activated EGFR. These EGFR-independent cancer cells, herein termed gefitinib-resistant (GR) cells, demonstrate higher levels of basal autophagy than their parental cells and thrive under hypoxic, reduced-serum conditions in vitro; this somewhat simulates the hypoxic environment common to cancerous tissues. We show that depletion of the essential autophagy gene, ATG5, by small interfering RNA (siRNA) or chloroquine, an autophagy inhibitor, markedly reduces GR cell viability under hypoxic conditions. Moreover, we show a significant elevation in caspase activity in GR cells following knockdown of ATG5. These results suggest that GR cells can evade apoptosis and survive in hostile, hypoxic environments with constant autophagic flux. We also show the presence of autophagosomes in some cancer cells from patient samples, even in untreated EGFR-mutant lung cancer tissue samples. Together, our results indicate that autophagy inhibitors alone or in combination with EGFR TKIs may be an effective approach for the treatment of EGFR-mutant lung cancers, where basal autophagy of some cancer cells is upregulated.

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“…Indeed, the use of an individual, genetically accurate patient-derived cell line has proven successful in several tumor models used recently by our group and others to discover clinically important mechanisms of resistance to targeted therapy in human tumors (4,(19)(20)(21). Continuous treatment of initially sensitive HCC364 BRAF V600E cells with vemurafenib resulted in the outgrowth of five sublines with acquired resistance (VR1-VR5, IC 50 >10 μM each) ( Fig.…”

Section: Mutant Braf Oncogene Dependence Is Variable and Transient Inmentioning

confidence: 99%

“…Filling this knowledge gap is critical, because the clinical success of driver oncogene-targeted therapies is limited by the almost inevitable escape from oncogene dependence and drug resistance that occur in patients with solid tumors, including lung cancer, the leading cause of cancer mortality worldwide (2,3). The identification of the signaling events driving resistance provides insights into the molecular mechanisms underlying oncogene dependence and a rationale for mechanism-based polytherapy strategies to subvert resistance in patients (2,4,5).…”

mentioning

confidence: 99%

Mapping the molecular determinants of BRAF oncogene dependence in human lung cancer

Asthana

Chan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Oncogenic mutations in the BRAF kinase occur in 6-8% of nonsmall cell lung cancers (NSCLCs), accounting for more than 90,000 deaths annually worldwide. The biological and clinical relevance of these BRAF mutations in NSCLC is incompletely understood. Here we demonstrate that human NSCLC cells with BRAF V600E , but not other BRAF mutations, initially are sensitive to BRAF-inhibitor treatment. However, these BRAF V600E NSCLC cells rapidly acquire resistance to BRAF inhibition through at least one of two discrete molecular mechanisms: (i) loss of full-length BRAF V600E coupled with expression of an aberrant form of BRAF V600E that retains RAF pathway dependence or (ii) constitutive autocrine EGF receptor (EGFR) signaling driven by c-Jun-mediated EGFR ligand expression. BRAF V600E cells with EGFR-driven resistance are characterized by hyperphosphorylated protein kinase AKT, a biomarker we validated in BRAF inhibitor-resistant NSCLC clinical specimens. These data reveal the multifaceted molecular mechanisms by which NSCLCs establish and regulate BRAF oncogene dependence, provide insights into BRAF-EGFR signaling crosstalk, and uncover mechanism-based strategies to optimize clinical responses to BRAF oncogene inhibition.targeted therapy | combination therapy

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Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer

Cited by 1,032 publications

References 29 publications

LAMC2 enhances the metastatic potential of lung adenocarcinoma

LAMC2 enhances the metastatic potential of lung adenocarcinoma

Enhanced autophagy is required for survival in EGFR-independent EGFR-mutant lung adenocarcinoma cells

Mapping the molecular determinants of BRAF oncogene dependence in human lung cancer

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