A Comprehensive Evaluation of Biomarkers Predictive of Response to PI3K Inhibitors and of Resistance Mechanisms in Head and Neck Squamous Cell Carcinoma

Abstract

The PI3K/AKT/mTOR pathway is frequently activated in head and neck squamous cell carcinoma (HNSCC), but pathway inhibition has variable efficacy. Identification of predictive biomarkers and mechanisms of resistance would allow selection of patients most likely to respond and novel therapeutic combinations. The purpose of this study was to extend recent discoveries regarding the PI3K/AKT/mTOR pathway in HNSCC by more broadly examining potential biomarkers of response, by examining pathway inhibitors with a diverse range of targets, and by defining mechanisms of resistance and potential combination therapies. We used reverse-phase protein arrays (RPPA) to simultaneously evaluate expression of 195 proteins; single-nucleotide polymorphism array to estimate gene copy number; and mass array to identify mutations. We examined altered signaling at baseline and after pathway inhibition. Likewise, we examined the activation of the PI3K/AKT/mTOR pathway in HNSCC tumors by RPPA. Cell lines with PIK3CA mutations were sensitive to pathway inhibitors, whereas amplification status did not predict sensitivity. While we identified a set of individual candidate biomarkers of response to pathway inhibitors, proteomic pathway scores did not correlate with amplification or mutation and did not predict response. Several receptor tyrosine kinases, including EGFR and ERK, were activated following PI3K inhibition in resistant cells; dual pathway inhibition of PI3K and EGFR or MEK demonstrated synergy. Combined MEK and PI3K inhibition was markedly synergistic in HRAS-mutant cell lines. Our findings indicate that clinical trials of single-agent PI3K/AKT/mTOR pathway inhibitors in selected populations and of PI3K-EGFR or PI3KMEK inhibitor combinations are warranted; we plan to conduct such trials.

Molecular Characterization of Apocrine Salivary Duct Carcinoma

“…Such an approach was shown to be synergistic in head and neck squamous cell carcinoma cell lines. 41 It has been previously shown that somatic missense TP53 mutations cause nuclear accumulation of the TP53 protein, whereas truncated TP53 proteins resulting from frameshift mutations lead to the loss of TP53 protein. 42 Here, TP53 IHC was used to corroborate the TP53 sequencing findings.…”

Targeting the PI3K/AKT/mTOR pathway in squamous cell carcinoma of the head and neck

“…In addition, experience with other successful targeted agents in cancer suggests that clinical resistance to PI3K pathway inhibitors may reduce the durability of clinical benefit [76]. A recent study using reverse-phase protein arrays indicated that the activation of RTKs, including EGFR and ERK, commonly occurred following PI3K inhibition in SCCHN cells resistant to PI3K pathway inhibitors [77]. In addition, combined inhibition of PI3K and EGFR or MEK pathways showed synergistic activity.…”

Genomics and advances towards precision medicine for head and neck squamous cell carcinoma

“…The PI3K‐AKT‐mTOR signaling pathway is a vital pathway for growth, survival, and metabolism for which there is evidence of frequent functional signal activation in HNSCC cell lines and tumors 25, 26, 27, 28, 29. Genetic aberrations such as CNAs, mutations, and dysregulation of mRNA are prevalent.…”