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

Abstract

e17509 Background: Head and neck squamous cell carcinomas (HNSCCs) are frequently altered along the PI3K/AKT/mTORC signaling axis leading to development of therapeutics targeting this pathway. Despite excellent preclinical data, the use of these compounds as monotherapy has been underwhelming in initial clinical trials and identification of predictive biomarkers remains challenging. The EGFR monoclonal antibody cetuximab remains the only approved targeted agent for HNSCC and has potential use in combination therapy. Methods: Both catalytic mTORC (AZD8055) and PI3K/mTORC(NVP-BEZ-235) inhibitors were tested +/- cetuximab in a panel of HNSCC cell lines and patient derived xenografts (PDX) evaluated for potential biomarkers of PI3K/AKT/mTORC pathway. Cell lines were assayed for response to all three agents by multiple approaches, and confirmed by siRNA knockdown. Five PDX models that presented PIK3CA mutation or intrinsic cetuximab resistance were treated with a combination of cetuximab and AZD8055. Results: In HNSCC cells no likely sensitizing mutations were identified, whereas putative protein biomarkers were elevated in some lines. All lines showed similar response to both PI3K/mTORC and dual mTORC inhibition with cetuximab combination producing modest additive effect with similar results for siRNA knockdown. In PDX models, in vivo single agent mTORC inhibition inhibited growth of a PIK3CA mutant cancer, but had little effect on any PIK3CAWT or a second PIK3CA mutant model. In all models the combination therapy showed greater growth delay than monotherapy. Conclusions: The uniform ability of PI3K and mTORC inhibition to suppress the growth of HNSCC cells highlights the pathway’s role in driving proliferation. In vivo, despite some PDX models meeting likely selection criteria, the single agent therapy was largely ineffective. Conversely improved response of combination treatment 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.

Selective inhibition of PI3K110α as a novel therapeutic strategy for cetuximab‑resistant oral squamous cell carcinoma

“…Although cetuximab is reported to have significant therapeutic efficacy against HNSCC (2,7,8), the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α isoform (PIK3CA) gene is a candidate gene involved in the acquired resistance to long-term cetuximab treatment due to point mutations within the gene (9)(10)(11). PIK3CA, a key element of the PI3K/AKT pathway ( Fig.…”