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AXL mediates resistance to PI3Kα inhibition by activating the EGFR/PKC/mTOR axis in head and neck and esophageal squamous cell carcinomas

Elkabets, Moshe and Scaltriti, Maurizio and Baselga, José and Sheng, Qing and Huang, Alan and Das, Rita and Wang, Hui-Qin and Liu, Manway and Liang, Jinsheng and Chen, Yan and Tam, Angela (2015) AXL mediates resistance to PI3Kα inhibition by activating the EGFR/PKC/mTOR axis in head and neck and esophageal squamous cell carcinomas. Cancer Cell, 27 (4). pp. 533-546. ISSN 15356108

Abstract

The p110α isoform of phosphatidylinositol-3-kinase (PI3K) (PI3Kα) is frequently aberrantly activated in squamous cell carcinoma of the head and neck (H&N) and esophagus, providing the rationale for PI3Kα inhibition in these malignancies. In this work we investigated the possible mechanisms of resistance to BYL719, a selective PI3Kα inhibitor currently in clinical development. Studying the differences between BYL719-sensitive and resistant cells we observed that sustained activity of mechanistic target of rapamycin (mTOR) upon therapy was sufficient to limit the sensitivity to PI3Kα inhibition. In resistant cells, overexpression of the tyrosine kinase receptor AXL and its binding to epidermal growth factor receptor (EGFR) leads to initiation of the phospholipase Cγ (PLCγ)- protein kinase C (PKC) cascade that in turn can activate mTOR in a PI3K/AKT-independent manner. Accordingly, inhibition of EGFR, AXL or PKC re-sensitized resistant cell lines to the antitumor activity of BYL719. Overall, our findings demonstrate that specific interaction of EGFR with AXL is capable to activate the PLCγ-PKC axis and overcome PI3K/AKT inhibition.

Item Type: Article
Date Deposited: 26 Apr 2016 23:45
Last Modified: 26 Apr 2016 23:45
URI: https://oak.novartis.com/id/eprint/23154

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