No abstract

The phosphoinositide 3-kinase (PI3K) signaling pathway is frequently mutated in head and neck squamous cell carcinoma (HNSCC), often via gain-of-function (GOF) mutations in the PIK3CA gene. Here we present novel genetically-engineered mouse models (GEMM) carrying a GOF allele Loxp-STOP-Loxp(LSL)-PIK3CA H1047R (E20) alone or in combination with heterozygous LSL-p53 +/R172H (p53) mutation with tissue-specific expression to interrogate the role of oncogenic PIK3CA in transformation of upper aerodigestive track epithelium. We demonstrated that the GOF PIK3CA mutation promoted progression of 4NQO-induced oral squamous cell carcinoma (OSCC) in both E20 single mutant and E20/p53 double mutant mice, with frequent distal metastasis detected only in E20/p53 GEMM. Similar to in human OSCC, loss of p16 was associated with progression of OSCC in these mice. RNA-Seq analyses revealed that among the common genes differentially expressed in primary OSCC cell lines derived from E20, p53, and E20/p53 GEMMs compared to those from the wild-type mice, genes associated with proliferation and cell cycle were predominantly represented, which is consistent with the progressive loss of p16 detected in these GEMMs. Importantly, all of these OSCC primary cell lines exhibited enhanced sensitivity to BYL719 and cisplatin combination treatment in comparison with cisplatin alone in vitro and in vivo, regardless of p53 and/or p16 status. Given the prevalence of mutations in p53 and the PI3K pathways in HNSCC in conjunction with loss of p16 genetically or epigenetically, this universal increased sensitivity to cisplatin and BYL719 combination therapy in cancer cells with PIK3CA mutation represents an opportunity to a subset of HNSCC patients. IMPLICATIONS:Our results suggest that combination therapy of cisplatin and PI3K inhibitor may be worthy of consideration in HNSCC patients with PIK3CA mutation.

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<p>Supplemental Figure Legends 1-4</p>

<p>Figure S1. Experimental scheme. Figure S2. Immunohistochemical analysis of the E20/p53 mouse. Figure S3. Representative YFP (+) metastatic cells isolated from the lymph node of an E20p53(YFP) double mutant mouse. Figure S4. Combination index calculation using COMPUSYN indicates a synergy between BYL719 and cisplatin in vitro in an E20/p53 SCC cell line, S24-658.</p>