Activation of the PIK3CA/AKT Pathway Suppresses Senescence Induced by an Activated RAS Oncogene to Promote Tumorigenesis

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2011 Apr 9

PMID 21474066

Citations 128

Authors

Alyssa L Kennedy

Jennifer P Morton

Indrani Manoharan

David M Nelson

Nigel B Jamieson

Jeff S Pawlikowski

Tony McBryan

Brendan Doyle

Colin McKay

Karin A Oien

Greg H Enders

Rugang Zhang

Owen J Sansom

Peter D Adams

Affiliations

Soon will be listed here.

Abstract

Mutations in both RAS and the PTEN/PIK3CA/AKT signaling module are found in the same human tumors. PIK3CA and AKT are downstream effectors of RAS, and the selective advantage conferred by mutation of two genes in the same pathway is unclear. Based on a comparative molecular analysis, we show that activated PIK3CA/AKT is a weaker inducer of senescence than is activated RAS. Moreover, concurrent activation of RAS and PIK3CA/AKT impairs RAS-induced senescence. In vivo, bypass of RAS-induced senescence by activated PIK3CA/AKT correlates with accelerated tumorigenesis. Thus, not all oncogenes are equally potent inducers of senescence, and, paradoxically, a weak inducer of senescence (PIK3CA/AKT) can be dominant over a strong inducer of senescence (RAS). For tumor growth, one selective advantage of concurrent mutation of RAS and PTEN/PIK3CA/AKT is suppression of RAS-induced senescence. Evidence is presented that this new understanding can be exploited in rational development and targeted application of prosenescence cancer therapies.

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