NSCLC depend upon YAP expression and nuclear localization after acquiring resistance to EGFR inhibitors.

Marc Mcgowan,Åslaug Hell,Odd Terje Brustugun,Lilach Kleinberg,Ann Rita Halvorsen

doi:10.18632/genesandcancer.136

Marc Mcgowan, Åslaug Hell + Show 3 more

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https://doi.org/10.18632/genesandcancer.136

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Journal: Genes & cancer	Publication Date: May 23, 2017
Citations: 47	License type: cc-by

Affiliation: Oslo University Hospital

Abstract

Yes-associated protein (YAP) is a downstream target of the Hippo pathway and has been found to be oncogenic driving many cancers into developing metastatic phenotypes leading to poor survival outcomes. This study investigated if YAP expression is associated with drug resistance in two non-small cell lung cancer (NSCLC) lines (HCC827 and H1975) generated to become resistant to the EGFR tyrosine kinase inhibitors (EGFR TKI) erlotinib, gefitinib or the T790M-specific osimertinib. We found that acquired EGFR TKI resistance was associated with YAP over-expression (osimertinib-resistant cells) or YAP amplification (erlotinib- and gefitinib-resistant cells) along with EMT phenotypic changes. YAP was localized in the nucleus, indicative of active protein. siRNA-mediated silencing of YAP resulted in re-sensitizing the drug-resistant cells to EGFR TKI compared to the negative siRNA controls (p = <0.05). These results suggest YAP is a potential mechanism of EGFR-TKI resistance in NSCLC and may presents itself as a viable therapeutic target.

Highlights

Innon-small cell lung cancer (NSCLC), responsible for the highest death toll among cancers [1], targeted therapy has been a remarkable success
We tested whether the third generation Epidermal growth factor receptor (EGFR) inhibitor osimertinib was able to inhibit growth in the drug-resistant sub-lines compared to the parental controls using the cell viability assay
In this report we show that induction of Yes-associated protein (YAP) is a possible mechanism of drug resistance to EGFR tyrosine kinase inhibitors in NSCLC adenocarcinomas, and that inhibiting this co-transcription factor can re-sensitize the cells to EGFR inhibitors

Summary

Introduction

Innon-small cell lung cancer (NSCLC), responsible for the highest death toll among cancers [1], targeted therapy has been a remarkable success. Both EGFR-, ALK-, ROS1 -directed therapies are approved, and about a fifth of all metastatic NSCLC patients may be offered such therapies with median responses of around a year [2]). A substantial fraction of tumours harbour other resistance mechanisms of which some, as AXL overexpression [6] and MET amplification [7, 8] are known, but others are still unknown and where no targeted therapies are available

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