PHGDH as a Key Enzyme for Serine Biosynthesis in HIF2?-Targeting Therapy for Renal Cell Carcinoma.

ABSTRACT: Continuous activation of hypoxia-inducible factor (HIF) is important for progression of renal cell carcinoma (RCC) and acquired resistance to antiangiogenic multikinase and mTOR inhibitors. Recently, HIF2? antagonists PT2385 and PT2399 were developed and are being evaluated in a phase I clinical trial for advanced or metastatic clear cell RCC (ccRCC). However, resistance to HIF2? antagonists would be expected to develop. In this study, we identified signals activated by HIF2? deficiency as candidate mediators of resistance to the HIF2? antagonists. We established sunitinib-resistant tumor cells in vivo and created HIF2?-deficient variants of these cells using CRISPR/Cas9 technology. Mechanistic investigations revealed that a regulator of the serine biosynthesis pathway, phosphoglycerate dehydrogenase (PHGDH), was upregulated commonly in HIF2?-deficient tumor cells along with the serine biosynthesis pathway itself. Accordingly, treatment with a PHGDH inhibitor reduced the growth of HIF2?-deficient tumor cells in vivo and in vitro by inducing apoptosis. Our findings identify the serine biosynthesis pathway as a source of candidate therapeutic targets to eradicate advanced or metastatic ccRCC resistant to HIF2? antagonists. Cancer Res; 77(22); 6321-9. ©2017 AACR.

SUBMITTER: Yoshino H 

PROVIDER: S-EPMC5893502 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature