Abstract B059: SETD2-PI3Kβ synthetic lethality

Abstract

Abstract Introduction: Renal cell carcinoma (RCC) is a high-risk and high-mortality cancer for which several new targeted therapies exist. However, responses of primary clear cell RCC (ccRCC) tumors and metastases to these targeted agents are variable, and complete responses are relatively uncommon, underscoring the need to identify reliable biomarkers to predict tumor behavior. Mutations in the tumor suppressor gene SETD2, encoding a lysine methyltransferase, occur in 3-16% of ccRCC tumors while the SETD2 protein deficiency rate has been reported to be as high as 34%. The phosphatidylinositide 3-kinases (PI3Ks) have emerged as important therapeutic targets for the treatment of solid and hematologic malignancies, including ccRCC. In this study, we determine the extent to which small-molecule inhibitors against the p110α, p110β, and p110δ isoforms of PI3K inhibit growth of RCC with SETD2 loss. Methods: RNAi oligonucleotides and small-molecule inhibitors targeting the p110α (BYL719), p110β (TGX221, AZD8186), and p110δ (idelalisib) isoforms of PI3K were tested against ccRCC cell lines with SETD2 loss. The effect of drugs on cell growth and survival was determined by (1) proliferation in monolayer, (2) 3D growth in Matrigel, and (3) cell migration in wound healing assay. Downstream signaling pathways were evaluated by immunoblot analysis. Results: Genetic and pharmacologic inhibition of p110β resulted in inhibition of ccRCC cell lines with SETD2 loss. ccRCC-derived SETD2 deficient (-/-) 786-O and A498 cells exhibited increased sensitivity to TGX221 (IC50 = 2.3 - 4.5 µM, respectively) and AZD8186 (IC50 = 1.79 - 0.24 µM, respectively) as compared to SETD2 proficient (+/+) 786-O cells (IC50 = >10 µM). Inhibition of the p110δ isoform alone had a modest effect on ccRCC cell growth and migration. Importantly, genetic (with siRNA) and pharmacologic (with BYL719) inhibition of p110α had no effect on the ccRCC cell lines. Inhibition of AKT with the small-molecule inhibitor MK2206 recapitulated the effects seen with AZD8186 in ccRCC cell lines with SETD2 loss, suggesting PI3Kβ mediates the synthetic lethality via AKT signaling in the context of SETD2 loss in ccRCC. Conclusions: Our work strongly suggests a synthetic lethal-type of interaction between PI3Kβ inhibition and SETD2 loss and offers a rationale for further translational and clinical investigation of small-molecule inhibitors of PI3Kβ in RCC. Xenograft studies are ongoing to investigate the in vivo efficacy of AZD8186. Citation Format: Esteban Terzo, Valerie M. Jansen, Yun-Chen Chiang, Kimryn W. Rathmell. SETD2-PI3Kβ synthetic lethality [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B059.