Co-targeting mTORC and EGFR signaling as a therapeutic strategy in HNSCC

Abstract

Head and neck squamous cell carcinomas (HNSCCs) are frequently altered along the PI3K/AKT/mTORC signaling axis. Despite excellent preclinical data, the use of compounds targeting this pathway as monotherapy has been underwhelming in initial clinical trials and identification of predictive biomarkers remains challenging. To investigate mTORC specific inhibition we tested catalytic mTORC (AZD8055) and PI3K/mTORC (NVP-BEZ-235) inhibitors +/− cetuximab in a panel of HNSCC cell lines and patient derived xenografts (PDX). Cell lines were assayed for response to all agents and siRNA knockdown of targets by multiple approaches. All cell lines showed similar response to both drug and siRNA inhibition of both PI3K and mTORC pathways, with anti-EGFR combination producing modest additive effect. Five PDX models that presented PIK3CA mutation or intrinsic cetuximab resistance were treated with a combination of cetuximab and AZD8055. In vivo single agent mTORC inhibition inhibited growth of a PIK3CA mutant cancer, but had little effect on any PIK3CA ^WT or a second PIK3CA mutant model. In all models the combination therapy showed greater growth delay than monotherapy. The uniform ability of PI3K and mTORC inhibition to suppress the growth of HNSCC cells highlights the pathway’s role in driving proliferation. While single agent therapy was largely ineffective in vivo, improved response of combination treatment in an array of PDXs suggests the potential for adding a catalytic mTORC inhibitor to cetuximab therapy. Overall, these results add to a growing body of evidence suggesting approaches that attempt to match biomarkers to the optimal therapy in HNSCC remains complex and challenging.