2 research outputs found
Snail Induces Mesenchymal Transition and Promotes EGFR TKI Resistance in NSCLC Cells Harboring EFGR Kinase Domain Mutations
Lung cancer is the leading cause of cancer related death, accounting for one third of all deaths from cancer worldwide. About 85-90% of lung cancers are non-small cell lung cancers (NSCLCs). Molecular targeted therapies such as epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) provide an effective treatment option for oncogene addicted NSCLC. However, the development of resistance to EGFR TKIs continues to be the major limitation in the treatment of NSCLC. Resistance to EGFR TKIs has been associated with the loss of canonical epithelial protein E-cadherin, suggesting involvement of epithelial to mesenchymal transition (EMT) in conferring EGFR TKI resistance. Transcription factors that regulate EMT may play a critical role in altering drug sensitivity of cancer cells. In this review we investigated the role of transcription factor SNAIL in affecting sensitivity of EGFR mutant NSCLC to EGFR TKIs
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CXCR7 Reactivates ERK Signaling to Promote Resistance to EGFR Kinase Inhibitors in NSCLC
Although EGFR mutant-selective tyrosine kinase inhibitors (TKI) are clinically effective, acquired resistance can occur by reactivating ERK. We show using in vitro models of acquired EGFR TKI resistance with a mesenchymal phenotype that CXCR7, an atypical G protein-coupled receptor, activates the MAPK-ERK pathway via β-arrestin. Depletion of CXCR7 inhibited the MAPK pathway, significantly attenuated EGFR TKI resistance, and resulted in mesenchymal-to-epithelial transition. CXCR7 overexpression was essential in reactivation of ERK1/2 for the generation of EGFR TKI-resistant persister cells. Many patients with non-small cell lung cancer (NSCLC) harboring an EGFR kinase domain mutation, who progressed on EGFR inhibitors, demonstrated increased CXCR7 expression. These data suggest that CXCR7 inhibition could considerably delay and prevent the emergence of acquired EGFR TKI resistance in EGFR-mutant NSCLC. SIGNIFICANCE: Increased expression of the chemokine receptor CXCR7 constitutes a mechanism of resistance to EGFR TKI in patients with non-small cell lung cancer through reactivation of ERK signaling