Activating Mutations in Pik3ca Contribute to Anal Carcinogenesis in the Presence or Absence of HPV-16 Oncogenes.

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)-trisphosphate kinase (PI3K), encoded by the Pik3ca gene, are detected in approximately 20% of human anal cancers.Experimental Design: We asked if common activating mutations in Pik3ca contribute 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 Pik3ca genes, 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 Pik3ca increased 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 Pik3ca mutations 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 vitro and reduced the growth rates of anal cancer-derived tumor grafts in vivo.

CONCLUSIONS:

These data demonstrate that activating mutations in Pik3ca drive anal carcinogenesis together with HPV16 oncogenes, and that the PI3K/mTOR pathway is a relevant target for therapeutic intervention.

• Authors: Myeong-Kyun Shin, Susan Payne, Andrea Bilger, Kristina A Matkowskyj, Evie Carchman, Dominique S Meyer, Mohamed Bentires-Alj, Dustin A Deming, Paul F Lambert
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 25 Issue 6 Pg. 1889-1900 (03 15 2019) ISSN: 1557-3265 [Electronic] United States
• PMID: 30530704 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Benzoxazoles
• Carcinogens
• Pyrimidines
• 9,10-Dimethyl-1,2-benzanthracene
• mTOR protein, mouse
• Class I Phosphatidylinositol 3-Kinases
• Pik3ca protein, mouse
• TOR Serine-Threonine Kinases
• sapanisertib

Topics

• 9,10-Dimethyl-1,2-benzanthracene (toxicity)
• Anal Canal (drug effects, pathology)
• Animals
• Anus Neoplasms (chemically induced, drug therapy, genetics, virology)
• Benzoxazoles (administration & dosage)
• Carcinogenesis (drug effects, genetics)
• Carcinogens (toxicity)
• Class I Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Female
• Gain of Function Mutation
• Human papillomavirus 16 (pathogenicity)
• Humans
• Mice
• Mice, Transgenic
• Neoplasms, Experimental (chemically induced, drug therapy, genetics, virology)
• Primary Cell Culture
• Pyrimidines (administration & dosage)
• Signal Transduction (drug effects, genetics)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Tumor Cells, Cultured