PHGDH as a Key Enzyme for Serine Biosynthesis in HIF2α-Targeting Therapy for Renal Cell Carcinoma

Cancer Res. 2017 Nov 15;77(22):6321-6329. doi: 10.1158/0008-5472.CAN-17-1589. Epub 2017 Sep 26.

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, HIF2α 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 HIF2α antagonists would be expected to develop. In this study, we identified signals activated by HIF2α deficiency as candidate mediators of resistance to the HIF2α antagonists. We established sunitinib-resistant tumor cells in vivo and created HIF2α-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 HIF2α-deficient tumor cells along with the serine biosynthesis pathway itself. Accordingly, treatment with a PHGDH inhibitor reduced the growth of HIF2α-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 HIF2α antagonists. Cancer Res; 77(22); 6321-9. ©2017 AACR.

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / antagonists & inhibitors*
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • CRISPR-Cas Systems
  • Carcinoma, Renal Cell / drug therapy*
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / metabolism
  • Cell Line, Tumor
  • Enzyme Inhibitors / pharmacology
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Indans / pharmacology
  • Kidney Neoplasms / drug therapy*
  • Kidney Neoplasms / genetics
  • Kidney Neoplasms / metabolism
  • Mice, Inbred BALB C
  • Mice, Nude
  • Molecular Targeted Therapy / methods
  • Phosphoglycerate Dehydrogenase / antagonists & inhibitors
  • Phosphoglycerate Dehydrogenase / genetics
  • Phosphoglycerate Dehydrogenase / metabolism*
  • Serine / biosynthesis*
  • Sulfones / pharmacology
  • Survival Analysis
  • Xenograft Model Antitumor Assays / methods*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Enzyme Inhibitors
  • Indans
  • PT2385
  • PT2399
  • Sulfones
  • endothelial PAS domain-containing protein 1
  • Serine
  • Phosphoglycerate Dehydrogenase