CHK1 protects oncogenic KRAS-expressing cells from DNA damage and is a target for pancreatic cancer treatment

Jennifer E. Klomp, Ye S. Lee, Craig M. Goodwin, Björn Papke, Jeff A. Klomp, Andrew M. Waters, Clint A. Stalnecker, Jonathan M. DeLiberty, Kristina Drizyte-Miller, Runying Yang, J. Nathaniel Diehl, Hongwei H. Yin, Mariaelena Pierobon, Elisa Baldelli, Meagan B. Ryan, Siqi Li, Jackson Peterson, Amber R. Smith, James T. Neal, Aaron K. McCormickCalvin J. Kuo, Christopher M. Counter, Emanuel F. Petricoin, Adrienne D. Cox, Kirsten L. Bryant, Channing J. Der*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

We apply genetic screens to delineate modulators of KRAS mutant pancreatic ductal adenocarcinoma (PDAC) sensitivity to ERK inhibitor treatment, and we identify components of the ATR-CHK1 DNA damage repair (DDR) pathway. Pharmacologic inhibition of CHK1 alone causes apoptotic growth suppression of both PDAC cell lines and organoids, which correlates with loss of MYC expression. CHK1 inhibition also activates ERK and AMPK and increases autophagy, providing a mechanistic basis for increased efficacy of concurrent CHK1 and ERK inhibition and/or autophagy inhibition with chloroquine. To assess how CHK1 inhibition-induced ERK activation promotes PDAC survival, we perform a CRISPR-Cas9 loss-of-function screen targeting direct/indirect ERK substrates and identify RIF1. A key component of non-homologous end joining repair, RIF1 suppression sensitizes PDAC cells to CHK1 inhibition-mediated apoptotic growth suppression. Furthermore, ERK inhibition alone decreases RIF1 expression and phenocopies RIF1 depletion. We conclude that concurrent DDR suppression enhances the efficacy of ERK and/or autophagy inhibitors in KRAS mutant PDAC.

Original languageEnglish
Article number110060
JournalCell Reports
Volume37
Issue number9
DOIs
StatePublished - 30 Nov 2021
Externally publishedYes

Keywords

  • CHK1
  • DNA damage
  • ERK
  • KRAS
  • MYC
  • RIF1
  • pancreatic cancer

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