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A whole genome CRISPR screen identifies AHR loss as a mechanism of resistance to a PARP7 inhibitor

ABSTRACT: Inhibitors directed towards PARP1 and PARP2 are approved agents for the treatment of BRCA-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. In fact, an inhibitor of PARP7 (RBN-2397) has now 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Minkyu Kim

LAB HEAD: Nevan Krogan

PROVIDER: PXD028733 | Pride | 2022-04-06

REPOSITORIES: Pride

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			Action	DRS
	HAP1_TurboID-PARP7.zip	Other
	MS_Sample_Annotatons__PARP7_TurboID_.xlsx	Xlsx
	qx019720.raw	Raw
	qx019721.raw	Raw
	qx019722.raw	Raw

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Publications

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

Chen Huadong H Diolaiti Morgan E ME O'Leary Patrick C PC Rojc Ajda A Krogan Nevan J NJ Kim Minkyu M Ashworth Alan A

Molecular cancer therapeutics 20220701 7

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 hydrocar ...[more]

PMID: 35439318

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