Selective Metabolic Dependencies in Kidney Cancer with Mitochondrial Mutations
Abstract
Chromophobe renal cell carcinoma (CRCC) accounts for 5 percent of RCC and the only treatment for patients is surgery. Mitochondrial deletions are common in these tumors and based on our previous work they might constitute a vulnerability in CRCC. We focus on whether inhibition of NADPH producing enzymes is a vulnerability in two CRCC cell lines using pharmacological and genetic tools in vitro and xenograft models. We have discovered that CRCC cells are more sensitive to the inhibition of NADPH production enzymes. We have used genetic and pharmacological inhibition of PPP pathway enzyme and ME1 finding that blocking these enzymes results in important cell death in CRCC cells. Importantly, the inhibition of PPP pathway enzyme causes sensitivity to ferroptosis inhibitors. Thus, we conclude that PPP pathway enzymes, alone or in combination with ferroptotic activators, are potential targets in CRCC.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2023
- Accession Number
- AD1215427
Entities
People
- Pere Puigserver i Burguera
Organizations
- Dana–Farber Cancer Institute