CCR-12-2716R2 4/3/13 PI3K-mTOR inhibitor PF-04691502 anti-tumor activity is enhanced with induction of wild-type TP53 in human xenograft and murine knockout models of head and neck cancer

Purpose: PI3K-mTOR pathway activation is often associated with altered expression or mutations of PIK3CA, TP53/p73, PTEN and TGFβR 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 9 HNSCC (UM-SCC) cell lines and Human Oral Keratinocytes (HOK). We investigated the molecular and anti-cancer effects of dual PI3K/mTOR inhibitor PF04691502(PF-502) in UM-SCC expressing PIK3CA with decreased wtTP53, mtTP53-/+ mtTGFΒR2, and in HNSCC of a conditional Pten/Tgfbr1 double knockout (2cKO) 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. Most UMSCC with wtTP53 exhibited a lower IC50 than those with mtTP53 status. PF-502 blocked growth in G0/G1 and increased apoptotic subG0 DNA. PF502 suppressed tumorigenesis and showed combinatorial activity with radiation in a wtTP53 UMSCC 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, 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 wtTP53. Research. on April 20, 2017. © 2013 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 2, 2013; DOI: 10.1158/1078-0432.CCR-12-2716