Abstract A09: Downregulation of PI3K signaling by high ERK activity prevents transformation by oncogenic RAS
Authors: Deschênes-Simard Xavier , Kottakis Filippos , Lessard Frédéric , Bardeesy Nabeel , Ferbeyre Gerardo 
Published: August 2014

In this study, we investigated the contribution of strong ERK signals to tumor suppression. Oncogenic forms of RAS are found in up to 30% of all human cancers and are established drivers of tumor initiation and maintenance. However, strong expression of these oncogenes in normal cells induces cellular senescence, a putative tumor-suppressive barrier. RAS activates several signaling pathways, such as the PI3K/AKT pathway, the RAL pathway and the classical RAF/MEK/ERK MAP Kinase pathway. We previously found that RASV12-induced senescence of primary cells is prevented by attenuation of ERK signaling. Mechanistically, strong ERK signaling promotes senescence by inducing selective proteasome-dependent protein degradation. This “Senescence-Associated Protein Degradation” (SAPD) targets proteins required for cell cycle progression, mitochondrial functions, cell migration and cell signaling.

Here we show that in addition to abrogating RAS-induced senescence, low ERK activity allows transformation of primary human cells stably expressing RasV12 and hTERT as well as transformation of RasV12-expressing rodent cells. Furthermore, in a Kras-driven mouse model of multistage pancreatic progression, decreased p-ERK levels correlate with tumor initiation. Taken together, these observations suggest that overactivated ERK may serve as a barrier for oncogenic transformation of cells acquiring activating RAS mutations. We found that the antitumor effects of aberrant ERK signaling include the inhibition of the phosphoinositide-3-kinase/AKT (PI3K/AKT) signaling pathway. Consequently, transformed RasV12-expressing cells with reduced ERK signaling show hyperactivation of the PI3K/AKT pathway, GSK3b inhibition, c-MYC stabilization and expression of stem cell-associated genes. In these cells, the hyperactivation of the PI3K/AKT pathway is essential in order to maintain their transformed phenotype since pharmacological inhibition of the pathway abrogates their tumorigenicity.

Collectively, these results demonstrate a novel anti-tumor effect of strong ERK signaling and suggest that processes attenuating ERK levels and/or activity may contribute to malignant transformation of oncogenic RAS-expressing cells. Therefore, we propose a model where a moderated level of activated ERK (p-ERK) in RAS-expressing cells promotes transformation whereas higher levels limit cancer initiation by activating tumor-supressive mechanisms. This model suggests caution in clinical use of inhibitors of the ERK-MAPK pathway. Although complete pathway shut-down may counter tumorigenesis, partial reductions in ERK signaling may be deleterious by allowing a bypass of tumor-suppressive mechanisms in other premalignant lesions or in cells with strong ERK activity.

Citation Format: Xavier Deschênes-Simard, Filippos Kottakis, Frédéric Lessard, Nabeel Bardeesy, Gerardo Ferbeyre. Downregulation of PI3K signaling by high ERK activity prevents transformation by oncogenic RAS. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr A09.