PI3K/mTOR inhibitor PF-04691502 antitumor activity is enhanced with induction of wild-type TP53 in human xenograft and murine knockout models of head and neck cancer.

ABSTRACT

PURPOSE: Phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway activation is often associated with altered expression or mutations of PIK3CA, TP53/p73, PTEN, and TGF-ß receptors (TGFBR) in head and neck squamous cell carcinomas (HNSCC). However, little is known about how these alterations affect response to PI3K/mTOR-targeted agents. EXPERIMENTAL DESIGN: In this preclinical study, PI3K/Akt/mTOR signaling was characterized in nine HNSCC (UM-SCC) cell lines and human oral keratinocytes. We investigated the molecular and anticancer effects of dual PI3K/mTOR inhibitor PF-04691502(PF-502) in UM-SCC expressing PIK3CA with decreased wild-type TP53, mutant TP53-/+ mutantTGFBR2, and in HNSCC of a conditional Pten/Tgfbr1 double knockout mouse model displaying PI3K/Akt/mTOR activation. RESULTS: UM-SCC showed increased PIK3CA expression and Akt/mTOR activation, and PF-502 inhibited PI3K/mTORC1/2 targets. In human HNSCC expressing PIK3CA and decreased wtTP53 and p73, PF-502 reciprocally enhanced TP53/p73 expression and growth inhibition, which was partially reversible by p53 inhibitor pifithrin-α. Most UM-SCC with wtTP53 exhibited a lower IC50 than those with mtTP53 status. PF-502 blocked growth in G0-G1 and increased apoptotic sub-G0 DNA. PF-502 suppressed tumorigenesis and showed combinatorial activity with radiation in a wild-type TP53 UM-SCC xenograft model. PF-502 also significantly delayed HNSCC tumorigenesis and prolonged survival of Pten/Tgfbr1-deficient mice. Significant inhibition of p-Akt, p-4EBP1, p-S6, and Ki67, as well as increased p53 and TUNEL were observed in tumor specimens. CONCLUSIONS: PI3K-mTOR inhibition can enhance TP53/p73 expression and significantly inhibit tumor growth alone or when combined with radiation in HNSCC with wild-type TP53. PIK3CA, TP53/p73, PTEN, and TGF-ß alterations are potential modifiers of response and merit investigation in future clinical trials with PI3K-mTOR inhibitors.