TY - JOUR T1 - Synthetic essentiality of metabolic regulator PDHK1 in PTEN-deficient cells and cancers JF - bioRxiv DO - 10.1101/441295 SP - 441295 AU - Nilanjana Chatterjee AU - Evangelos Pazarentzos AU - Gorjan Hrustanovic AU - Luping Lin AU - Erik Verschueren AU - Jeffrey R. Johnson AU - Matan Hofree AU - Jenny J. Yan AU - Victor Olivas AU - Billy W. Newton AU - John V. Dollen AU - Charles H. Earnshaw AU - Jennifer Flanagan AU - Elton Chan AU - Saurabh Asthana AU - Trey Ideker AU - Wei Wu AU - Manasi K. Mayekar AU - Junji Suzuki AU - Ben Barad AU - Yuriy Kirichok AU - James Fraser AU - William A. Weiss AU - Nevan J. Krogan AU - Asmin Tulpule AU - Amit J. Sabnis AU - Trever G. Bivona Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/10/11/441295.abstract N2 - PTEN is a tumor suppressor that is often inactivated in cancer and possesses both lipid and protein phosphatase activities. We report the metabolic regulator PDHK1 (pyruvate dehydrogenase kinase1) is a synthetic-essential gene in PTEN-deficient cancer and normal cells. The predominant mechanism of PDHK1 regulation and dependency is the PTEN protein phosphatase dephosphorylates NFκ;B activating protein (NKAP) and limits NFκB activation to suppress expression of PDHK1, a NFκB target gene. Loss of the PTEN protein phosphatase upregulates PDHK1 to drive aerobic glycolysis and induce PDHK1 cellular dependence. PTEN-deficient human tumors harbor increased PDHK1, which is a biomarker of decreased patient survival, establishing clinical relevance. This study uncovers a PTEN-regulated signaling pathway and reveals PDHK1 as a potential target in PTEN-deficient cancers.SIGNIFICANCE The tumor suppressor PTEN is widely inactivated in cancers and tumor syndromes. PTEN antagonizes PI3K/AKT signaling via its lipid phosphatase activity. The modest success of PI3K/AKT inhibition in PTEN-deficient cancer patients provides rationale for identifying other vulnerabilities in PTEN-deficient cancers to improve clinical outcomes. We show that PTEN-deficient cells are uniquely sensitive to PDHK1 inhibition. PTEN and PDHK1 co-suppression reduced colony formation and induced cell death in vitro and tumor regression in vivo. PDHK1 levels were high in PTEN-deficient patient tumors and associated with inferior patient survival, establishing clinical relevance. Our study identifies a PTEN-regulated signaling pathway linking the PTEN protein phosphatase to the metabolic regulator PDHK1 and provides a mechanistic basis for PDHK1 targeting in PTEN-deficient cancers. ER -