Oncotarget

Research Papers:

This article has been corrected. Correction in: Oncotarget. 2019; 10:6391-6392.

SETD2 loss sensitizes cells to PI3Kβ and AKT inhibition

Esteban A. Terzo, Aaron R. Lim, Anna Chytil, Yun Chen Chiang, Leah Farmer, Kathryn H. Gessner, Cheryl Lyn Walker, Valerie M. Jansen and W. Kimryn Rathmell _

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Abstract

Esteban A. Terzo1,5,*, Aaron R. Lim1,2,*, Anna Chytil1, Yun Chen Chiang3,6, Leah Farmer1, Kathryn H. Gessner3, Cheryl Lyn Walker4, Valerie M. Jansen1,7,# and W. Kimryn Rathmell1,#

1Vanderbilt-Ingram Cancer Center, Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville 37232, TN, USA

2Medical Scientist Training Program, Vanderbilt University School of Medicine, Nashville 37232, TN, USA

3Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill 27599, NC, USA

4Center for Precision Environmental Health, Baylor College of Medicine, Houston 77030, TX, USA

5Current Address: Constellation Pharmaceuticals, Cambridge, MA, USA

6Current Address: Novella/IQVIA, Morrisville, NC, USA

7Current Address: Eli Lilly and Company, Indianapolis, IN, USA

*Co-first authors

#Co-corresponding authors

Correspondence to:

W. Kimryn Rathmell, email: Kimryn.Rathmell@vumc.org

Keywords: SETD2; PI3Kβ; synthetic lethality; renal cell carcinoma

Received: July 18, 2018     Accepted: December 22, 2018     Published: January 18, 2019

ABSTRACT

Upregulation of the PI3K pathway has been implicated in the initiation and progression of several types of cancer, including renal cell carcinoma (RCC). Although several targeted therapies have been developed for RCC, durable and complete responses are exceptional. Thus, advanced RCC remains a lethal disease, underscoring the need of robust biomarker-based strategies to treat RCC. We report a synthetic lethal interaction between inhibition of phosphatidylinositol 3-kinase beta (PI3Kβ) and loss of SETD2 methyltransferase. Clear cell RCC (ccRCC)-derived SETD2 knockout 786-0 and SETD2 mutant A498 cells treated with TGX221 (PI3Kβ-specific) and AZD8186 (PI3Kβ- and δ-specific) inhibitors displayed decreased cell viability, cell growth, and migration compared to SETD2 proficient 786-0 cells. Inhibition of the p110 δ and α isoforms alone had modest (δ) and no (α) effect on ccRCC cell viability, growth, and migration. In vivo, treatment of SETD2 mutant A498 cells, but not SETD2 proficient 786-0 cells, with AZD8186 significantly decreased tumor growth. Interestingly, inhibition of the downstream effector AKT (MK2206) recapitulated the effects observed in AZD8186-treated SETD2 deficient cells. Our data show that specific inhibition of PI3Kβ causes synthetic lethality with SETD2 loss and suggest targeting of the AKT downstream effector pathway offers a rationale for further translational and clinical investigation of PI3Kβ-specific inhibitors in ccRCC.


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