Abstract A53: Akt inhibitior MK2206 combination to neoadjuvant radiotherapy: Improving the rectal cancer treatment

Abstract

Resistance to therapy is the major obstacle to a favorable outcome in cancer treatment. Neoadjuvant chemoradiotherapy (nCRT) can lead to complete tumor regression in a significant proportion of patients with rectal cancer (up to 40%). The possibility of avoiding radical surgery and its associated functional consequences for those who present complete response has become increasingly attractive, but approximately 60% of patients have only partial or no tumor remission after nCRT. In order to identify molecular mechanisms determining poor response to nCRT and to uncover optimized treatment strategies, we have conducted global gene expression analysis followed by pathway enrichment analysis in pretreatment biopsies from patients showing complete or poor clinical response to nCRT. We show that mitochondrial oxidative phosphorylation and phosphatidylinositol signaling pathways are consistently altered in rectal tumors comparatively. Both pathways have already been associated with resistance to radiation and chemotherapy in solid tumors and appear to converge on the activation of the Akt pathway in nonresponding tumors. To further address the role of Akt activation in response to nCRT, we evaluated by immunohistochemistry, Akt activation in an independent set of pretreatment biopsies from rectal cancer patients and observed not only high pAkt levels in those presenting poor response to nCRT but also that nuclear pAkt can also discriminate resistant tumors. We also evaluated the combination of an allosteric Akt-inhibitor MK2206 to chemoradiation in a radioresistant colorectal cancer cell line SW480 either in vitro and in vivo and observed an improvement of 50% of tumoricidal effect. Altogether, our results indicate that activation of the Akt pathway is a key event affecting response to nCRT and that combining chemoradiotherapy and Akt inhibitors such as MK2206 may significantly improve response rates to neoadjuvant therapy in rectal cancer. Citation Format: Fernanda C. Koyama, Camila M. Lopes Ramos, Jennifer M. Fernandes, Fernanda C. Ledesma, Venancio A F Alves, Fernanda C. Vailati, Angelita Habr-Gama, Rodrigo O. Perez, Anamaria A. Camargo. Akt inhibitior MK2206 combination to neoadjuvant radiotherapy: Improving the rectal cancer treatment [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr A53.