Cotargeting 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 PIK3CAWT 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.

Patient Derived Models to Study Head and Neck Cancer Radiation Response

“…PDXs are a valuable resource for evaluating therapeutic response and for confirming putative mechanisms identified in other model systems [7,8,[25][26][27][28]. Most PDXs established by our lab, and others, utilize remnant tissue provided by pathology after surgical excision of the cancer (discussed more below).…”

Patient Derived Models to Study Head and Neck Cancer Radiation Response

“…PDXs are a valuable resource for evaluating therapeutic response and for confirming putative mechanisms identified in other model systems [5,6,[20][21][22][23]. Most PDXs established by our lab, and others, utilize remnant tissue provided by pathology after surgical excision of the cancer (discussed more below).…”

Novel DNA targeted therapies for head and neck cancers: clinical potential and biomarkers

“…As discussed previously, PI3K inhibitors as monotherapy have limited effect due to the compensatory feedback via other pathways like RAS/RAF/MEK/ERK. This can be addressed by combining PI3K inhibitors with DNA damaging therapies or Cetuximab, which results in dramatic growth inhibition via an anti-proliferative effect rather than a pro-death action [ 80 ]. Secondly, PI3K inhibition can induce mitochondrial reprogramming that will promote tumor invasion and progression.…”

“…This lack of patient stratification can have tremendous effects on response to targeted therapies. Evidently there is room for improvement, combining PI3K inhibitors with other DNA damaging therapies or Cetuximab may have clinical benefit regardless of the mutational status [ 80 ]. To improve the success of PI3K inhibitors, pharmacological, biological and translational issues must be better identified.…”