CRISPR screening identifies BET and mTOR inhibitor synergy in cholangiocarcinoma through serine glycine one carbon

Yan Zhu, Dengyong Zhang, Pooja Shukla, Young Ho Jung, Prit Benny Malgulwar, Sharmeen Chagani, Medina Colic, Sarah Benjamin, John A. Copland, Lin Tan, Philip L. Lorenzi, Milind Javle, Jason T. Huse, Jason Roszik, Traver Hart, Lawrence N. Kwong

Research output: Contribution to journalArticlepeer-review

Abstract

Patients with cholangiocarcinoma have poor clinical outcomes due to late diagnoses, poor prognoses, and limited treatment strategies. To identify drug combinations for this disease, we have conducted a genome-wide CRISPR screen anchored on the bromodomain and extraterminal domain (BET) PROTAC degrader ARV825, from which we identified anticancer synergy when combined with genetic ablation of members of the mTOR pathway. This combination effect was validated using multiple pharmacological BET and mTOR inhibitors, accompanied by increased levels of apoptosis and cell cycle arrest. In a xenograft model, combined BET degradation and mTOR inhibition induced tumor regression. Mechanistically, the 2 inhibitor classes converged on H3K27acmarked epigenetic suppression of the serine glycine one carbon (SGOC) metabolism pathway, including the key enzymes PHGDH and PSAT1. Knockdown of PSAT1 was sufficient to replicate synergy with single-agent inhibition of either BET or mTOR. Our results tie together epigenetic regulation, metabolism, and apoptosis induction as key therapeutic targets for further exploration in this underserved disease.

Original languageEnglish (US)
Article numbere174220
JournalJCI Insight
Volume9
Issue number2
DOIs
StatePublished - Jan 2024

ASJC Scopus subject areas

  • General Medicine

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