AXL mediates resistance to PI3Ka inhibition by activating the EGFR/PKC/mTOR axis in head and neck and esophageal squamous cell carcinomas.

Phosphoinositide-3-kinase (PI3K)-a inhibitors are clinically active in squamous carcinoma (SCC) of the head and neck (H&N) bearing mutations or amplification of PIK3CA. We aimed to identify potential mechanism of resistance and have observed that SCCs cells overcome the antitumor effects of the PI3Ka inhibitor BYL719 by maintaining PI3K-independent activation of the mammalian target of rapamycin (mTOR). The persistent mTOR activation is mediated by the tyrosine kinase receptor AXL. We found that AXL is overexpressed in resistant tumors, dimerizes with the epidermal growth factor receptor (EGFR), phosphorylates EGFR tyrosine 1173, resulting in activation of phospholipase C? (PLC?)- protein kinase C (PKC) that, in turn, activates mTOR. Finally, simultaneous treatment with PI3Ka and either EGFR, AXL or PKC inhibitors reverts this resistance. Overall design: RNAseq from acquired resistant cells CAL33B, K180B were compared to their parental counterpart CAL33 and K180, respectively. K180 is a shortcut of KYSE180, and B stands for BYL719. Duplicate of parental sensitive cells and K180B, and triplicate for CAL33B.

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Elkabets M, Pazarentzos E, Juric D, Sheng Q, Pelossof RA, Brook S, Benzaken AO, Rodon J, Morse N, Yan JJ, Liu M, Das R, Chen Y, Tam A, Wang H, Liang J, Gurski JM, Kerr DA, Rosell R, Teixidó C, Huang A, Ghossein RA, Rosen N, Bivona TG, Scaltriti M, Baselga J