Abstract 4317: PTEN-null tumors cohabiting the same lung display differential Akt activation and sensitivity to dietary restriction.

Abstract

Abstract PTEN loss is considered a biomarker for activated PI3K/Akt, a pathway frequently mutated in cancer, and recently shown to confer resistance to dietary restriction (DR). Here we demonstrate that PTEN loss is not sufficient to drive Akt activation and resistance to DR in tumors with low growth factor receptor levels. We describe a murine PTEN-null Kras-driven lung cancer model that harbors both DR-resistant, higher-grade, bronchiolar tumors with high-Akt-activity, and DR-sensitive, lower-grade, alveolar tumors with low-Akt-activity. We find that this phenotype is cell-autonomous and that normal bronchiolar cells express higher levels of IGF1R and ENTPD5, an endoplasmic reticulum (ER) enzyme known to modulate growth factor receptor levels. Suppression of ENTPD5 is sufficient to decrease IGF1R levels and sensitize bronchiolar tumor cells to serum in vitro and to DR in vivo. Furthermore, we find that a significant percentage of human non-small cell lung cancer (NSCLC) have low Akt activity despite PTEN loss. Our studies point to a heterogeneity of Akt activation in the same murine PTEN-null lung tissue, as well as in human NSCLC, underscoring the challenges facing personalized cancer therapy based solely on cancer genotype. They further indicate that the tumor response to anti-cancer therapies, including DR, needs to be based upon PI3K/Akt activity per se, rather than genetic alterations in the PTEN/Akt pathway. Citation Format: Natasha L. Curry, Mari Mino-Kenudson, Trudy G. Oliver, Omer H. Yilmaz, Vedat O. Yilmaz, Jade Moon, Tyler Jacks, David M. Sabatini, Nada Y. Kalaany. PTEN-null tumors cohabiting the same lung display differential Akt activation and sensitivity to dietary restriction. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4317. doi:10.1158/1538-7445.AM2013-4317