4.5 Article

Multiple cancers escape from multiple MAPK pathway inhibitors and use DNA replication stress signaling to tolerate aberrant cell cycles

Journal

SCIENCE SIGNALING
Volume 16, Issue 796, Pages -

Publisher

AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.ade8744

Keywords

-

Ask authors/readers for more resources

Many cancers with pro-proliferative mutations in the MAPK pathway can rapidly escape the effects of MAPK pathway inhibitors. Cancer cells driven by BRAF, EGFR, or KRAS mutations can adapt and resume slow proliferation after being treated with these inhibitors. The escape of cells is associated with DNA replication deficits, DNA lesions, and stress responses that rely on the ATR kinase. The recruitment of components from the FA DNA repair pathway enables the successful completion of cell division in escapee cells.
Many cancers harbor pro-proliferative mutations of the mitogen-activated protein kinase (MAPK) pathway. In BRAF-driven melanoma cells treated with BRAF inhibitors, subpopulations of cells escape drug-induced quiescence through a nongenetic manner of adaptation and resume slow proliferation. Here, we found that this phenomenon is common to many cancer types driven by EGFR, KRAS, or BRAF mutations in response to multiple, clinically approved MAPK pathway inhibitors. In 2D cultures and 3D spheroid models of various cancer cell lines, a subset of cells escaped drug-induced quiescence within 4 days to resume proliferation. These escapee cells exhibited DNA replication deficits, accumulated DNA lesions, and mounted a stress response that depended on the ataxia telangiectasia and RAD3-related (ATR) kinase. We further identified that components of the Fanconi anemia (FA) DNA repair pathway are recruited to sites of mitotic DNA synthesis (MiDAS) in escapee cells, enabling successful completion of cell division. Analysis of patient tumor samples and clinical data correlated disease progression with an increase in DNA replication stress response factors. Our findings suggest that many MAPK pathway-mutant cancers rapidly escape drug action and that suppressing early stress tolerance pathways may achieve more durable clinical responses to MAPK pathway inhibitors.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.5
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available