A Whole-Genome CRISPR Screen IdentifiesAHRLoss as a Mechanism of Resistance to a PARP7 Inhibitor

Huadong Chen, Morgan E. Diolaiti, Patrick C. O'Leary, Ajda Rojc, Nevan J. Krogan, Minkyu Kim, Alan Ashworth

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Inhibitors directed toward PARP1 and PARP2 are approved agents for the treatment of BRCA1 and BRCA2-related cancers. Other members of the PARP family have also been implicated in cancer and are being assessed as therapeutic targets in cancer and other diseases. Recently, an inhibitor of PARP7 (RBN-2397) has reached early-stage human clinical trials. Here, we performed a genome-wide CRISPR screen for genes that modify the response of cells to RBN-2397. We identify the polycyclic aromatic hydrocarbon receptor AHR and multiple components of the cohesin complex as determinants of resistance to this agent. Activators and inhibitors of AHR modulate the cellular response to PARP7 inhibition, suggesting potential combination therapy approaches.

Original languageEnglish (US)
Pages (from-to)1076-1089
Number of pages14
JournalMolecular cancer therapeutics
Volume21
Issue number7
DOIs
StatePublished - Jul 2022
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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