Abstract 1200: Oncogenic KRAS sensitizes colorectal tumor cells to chemotherapy via p53-dependent induction of Noxa

Abstract

Abstract Oxaliplatin and 5-fluorouracil currently form the backbone of conservative treatment in patients with metastatic colorectal cancer. Tumor responses to these agents are highly variable, but the underlying mechanisms are poorly understood. Our previous results have indicated that the presence of oncogenic KRAS in colorectal tumor cells sensitizes these cells to chemotherapy. In the present manuscript we show that the sensitization of colorectal tumor cells to oxaliplatin and 5-FU by oncogenic KRAS is critically dependent on the presence of wild type p53. KRAS status did not influence p53 stabilization, p21 induction, or cell cycle arrest. A screen for induction of apoptosis regulators revealed that KRAS selectively promoted expression of the pro-apoptotic p53 target gene Noxa. Suppression of Noxa by RNA interference strongly reduced KRAS/p53-dependent apoptosis following exposure to chemotherapy, both in vitro and in tumor xenografts in mice. Noxa knockdown did not affect p53-dependent p21 induction or cell cycle arrest. Our results identify oncogenic KRAS as an important determinant of the cellular response to p53 activation following exposure to oxaliplatin or 5-FU, by facilitating apoptosis induction through Noxa. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1200.