Activating Mutations in Pik3caContribute to Anal Carcinogenesis in the Presence or Absence of HPV-16 Oncogenes.

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Activating Mutations in Pik3caContribute to Anal Carcinogenesis in the Presence or Absence of HPV-16 Oncogenes.

Clin Cancer Res. 2018 Dec 07;:

Authors: Shin MK, Payne SN, Bilger A, Matkowskyj KA, Carchman E, Meyer DS, Bentires-Alj M, Deming DA, Lambert PF

Abstract
PURPOSE: Over 95% of human anal cancers are etiologically associated with high-risk HPVs, with HPV type 16 (HPV16) the genotype most commonly found. Activating mutations in the catalytic subunit of Phosphatidylinositol (3,4,5)-trisphosphatekinase (PI3K), encoded by the Pik3cagene, are detected in approximately 20% of human anal cancers.
EXPERIMENTAL DESIGN: We asked if common activating mutations in Pik3cacontribute to anal carcinogenesis using an established mouse model for anal carcinogenesis in which mice are topically treated with the chemical carcinogen 7,12-Dimethylbenz(a)anthracene (DMBA). Mice expressing in their anal epithelium one of two activating mutations in Pik3cagenes, Pik3caH1047R or Pik3caE545K , were monitored for anal carcinogenesis in the presence or absence of transgenes expressing the HPV16 E6 and E7 oncogenes.
RESULTS: Both mutant forms of Pik3caincreased susceptibility to anal carcinogenesis in the absence of HPV16 oncogenes, and cooperated with HPV16 oncogenes to induce the highest level and earliest onset of anal cancers. The combination of HPV16 oncogenes and Pik3camutations led to anal cancers even in the absence of treatment with DMBA. We further observed that the investigational mTOR1/2 dual inhibitor, TAK-228, significantly reduced the size of anal cancer-derived tumor spheroids in vitroand reduced the growth rates of anal cancer-derived tumor grafts in vivo Conclusion:These data demonstrate that activating mutations in Pik3cadrive anal carcinogenesis together with HPV16 oncogenes, and that the PI3K/mTOR pathway is a relevant target for therapeutic intervention.

PMID: 30530704 [PubMed - as supplied by publisher]

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