AI Article Synopsis

  • The T790M mutation in EGFR leads to resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in lung cancer, particularly in non-small cell lung cancer (NSCLC) patients.
  • High expression of the Hippo pathway effector TAZ in NSCLC cells with the T790M mutation was found to contribute to this resistance, as depleting TAZ made cells more sensitive to EGFR-TKIs.
  • Targeting both the EGFR mutation and TAZ may offer a better treatment strategy for overcoming resistance to EGFR-TKIs in NSCLC patients.

Article Abstract

Background: The T790M mutation of epithelial growth factor receptor (EGFR) is a major cause of the acquired resistance to EGFR tyrosine kinase inhibitor (EGFR-TKIs) treatment for lung cancer patients. The Hippo pathway effector, TAZ, has emerged as a key player in organ growth and tumorigenesis, including lung cancer.

Results: In this study, we have discovered high TAZ expression in non-small cell lung cancer (NSCLC) cells harboring dual mutation and TAZ depletion sensitized their response to EGFR-TKIs. Mechanistically, knockdown of TAZ in T790M-induced resistant cells leaded to reduced anchorage-independent growth in vitro, tumor formation and resistance to gefitinib in vivo, correlated with epithelial-mesenchymal transition (EMT) and suppressed migration and invasion. Furthermore, we confirmed CTGF and AXL, novel EMT markers and potential therapeutic targets for overcoming EGFR inhibitor resistance, as directly transcriptional targets of TAZ.

Conclusions: Taken together, this study suggests that expression of TAZ is an intrinsic mechanism of T790M-induced resistance in response to EGFR-TKIs. Combinational targeting on both EGFR and TAZ may enhance the efficacy of EGFR-TKIs in acquired resistance of NSCLC.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4429831PMC
http://dx.doi.org/10.1186/2045-3701-5-7DOI Listing

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