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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) presents significant therapeutic challenges.
• ERK signaling pathways are implicated in PDAC cell survival and proliferation.
• DNA damage repair (DDR) pathways are potential targets for cancer therapy.

Purpose of the Study:

• To identify modulators of KRAS-mutant PDAC sensitivity to ERK inhibitors.
• To investigate the role of the ATR-CHK1 DDR pathway in PDAC.
• To explore combination therapies involving DDR, ERK, and autophagy inhibition.

Main Methods:

• Genetic screens to identify modulators of PDAC sensitivity to ERK inhibitors.
• Pharmacologic inhibition of CHK1 in PDAC cell lines and organoids.
• CRISPR-Cas9 loss-of-function screens to identify ERK substrates.
• Analysis of gene expression (MYC), protein activation (ERK, AMPK), and autophagy markers.

Main Results:

• Components of the ATR-CHK1 DDR pathway were identified as modulators of PDAC sensitivity.
• CHK1 inhibition induced apoptosis, suppressed MYC expression, activated ERK and AMPK, and increased autophagy.
• RIF1 was identified as an ERK substrate; its suppression sensitized PDAC cells to CHK1 inhibition.
• ERK inhibition decreased RIF1 expression, mimicking RIF1 depletion effects.

Conclusions:

• Concurrent suppression of DNA damage repair pathways enhances the efficacy of ERK and/or autophagy inhibitors in KRAS-mutant PDAC.
• The interplay between CHK1 inhibition, ERK activation, RIF1, and autophagy provides a rationale for combination therapies.
• Targeting the ATR-CHK1 pathway alongside ERK or autophagy inhibition represents a promising therapeutic strategy for PDAC.