A Whole-Genome CRISPR Screen Identifies AHR Loss as a Mechanism of Resistance to a PARP7 Inhibitor

  • Mol Cancer Ther. 2022 Jul 5;21(7):1076-1089. doi: 10.1158/1535-7163.MCT-21-0841.
Huadong Chen  1 ,  Morgan E Diolaiti  1  2 ,  Patrick C O'Leary  1  2 ,  Ajda Rojc  2  3  4  5 ,  Nevan J Krogan  2  3  4  5 ,  Minkyu Kim  2  3  4  5 ,  Alan Ashworth  1  2
Affiliations
  • 1. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
  • 2. The Cancer Cell Map Initiative, San Francisco and La Jolla, California.
  • 3. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California.
  • 4. The J. David Gladstone Institute of Data Science and Biotechnology, San Francisco, California.
  • 5. Quantitative Biosciences Institute, University of California, San Francisco, California.
PMID: 35439318 DOI: 10.1158/1535-7163.MCT-21-0841
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.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-136174
    RBN-2397
    99.82%, PARP7 Inhibitor
    target: PARP
    Research Areas: Cancer