Abstract 1713: PDK1 and hexokinase 2 are downstream effectors of PTEN loss and regulate response to targeted therapies in multiple tumor types

Abstract

Abstract Recent advances in molecular profiling of many human tumor types has enabled the development and clinical use of molecularly-targeted therapies in patients. Many tumors exhibit inactivation of PTEN which is predicted to sensitize tumor cells to PI3 kinase or AKT inhibitor therapy. However, clinical responses to PI3 kinase or AKT inhibitors are variable and not curative. Furthermore, these responses in patients do not correlate uniformly with PTEN inactivation. Therefore, we investigated whether PTEN inactivation could lead to dependence on signaling pathways and components that function independently of PI3K or AKT and that could serve as novel therapeutic targets in PTEN deficient tumors. Using multiple human tumor models including lung adenocarcinoma, lung squamous, renal cell carcinoma, and prostate adenocarcinoma that express or lack PTEN and Gene Set Enrichment Analysis, we identified alterations in numerous metabolic regulatory genes in response to PTEN inactivation, including hexokinase 2 (HK2) and pyruvate dehydrogenase kinase 1 (PDK1). We found that in PTEN-deficient tumor cells HK2 is upregulated and selectively localizes to the mitochondria, where it enhances glycolytic flux and inhibits apoptosis. Furthermore, we found that PDK1 is also upregulated upon PTEN inactivation and suppresses oxidative phosphorylation, upregulating glycolysis and the production of lactate. Thus, we uncovered a novel role for HK2 and PDK1 in the metabolic reprogramming that occurs as a consequence of PTEN inactivation in tumor cells. Furthermore, we found that overexpression of either HK2 or PDK1 confers resistance to targeted therapies against PI3K and other oncogenic drivers more broadly. Conversely, genetic or pharmacological suppression of HK2 or PDK1 enhances response to targeted therapy in multiple tumor cell types. Together, our data identify HK2 and PDK1 as novel molecular biomarkers and promising therapeutic targets in multiple PTEN deficient tumor types. Citation Format: Evangelos Pazarentzos, Trever G. Bivona. PDK1 and hexokinase 2 are downstream effectors of PTEN loss and regulate response to targeted therapies in multiple tumor types. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1713. doi:10.1158/1538-7445.AM2014-1713