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Published on: September 1, 2019
Multiple cancers escape from multiple MAPK pathway inhibitors and use DNA replication stress signaling to tolerate
Timothy E Hoffman1, Varuna Nangia1,2, C Ryland Ill1
1Department of Biochemistry and Biofrontiers Institute, University of Colorado Boulder, Boulder, CO 80303, USA.
Abstract:
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.
Insights
Many MAPK pathway-mutant cancers adapt to BRAF inhibitors by resuming proliferation. DNA repair pathways help these "escapee" cells survive, suggesting new therapeutic targets for durable cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Many cancers possess mutations in the mitogen-activated protein kinase (MAPK) pathway, driving tumor growth.
- MAPK pathway inhibitors are clinically approved treatments, but cancer cells can develop resistance.
- Cancer cells can adapt to drug treatment through non-genetic mechanisms, resuming proliferation.
Purpose of the Study:
- To investigate the common mechanisms of drug resistance in MAPK pathway-mutant cancers.
- To identify the cellular pathways involved in cancer cell adaptation to MAPK inhibitors.
- To explore therapeutic strategies for overcoming drug resistance and achieving durable responses.
Main Methods:
- Utilized 2D and 3D cell culture models of various cancer cell lines with EGFR, KRAS, or BRAF mutations.
- Administered clinically approved MAPK pathway inhibitors to assess cellular responses.
- Analyzed DNA replication, DNA damage, stress responses (ATR kinase), and DNA repair pathways (Fanconi anemia).
- Examined patient tumor samples and clinical data to correlate findings with disease progression.
Main Results:
- A subset of cancer cells escaped drug-induced quiescence and resumed proliferation within 4 days.
- These 'escapee' cells showed DNA replication deficits and accumulated DNA lesions, activating an ATR kinase-dependent stress response.
- Components of the Fanconi anemia DNA repair pathway were recruited to sites of mitotic DNA synthesis (MiDAS) in escapee cells.
- Increased DNA replication stress response factors correlated with disease progression in patient data.
Conclusions:
- MAPK pathway-mutant cancers commonly exhibit rapid, non-genetic adaptation to MAPK inhibitors.
- The Fanconi anemia DNA repair pathway plays a crucial role in enabling proliferation of drug-adapted cancer cells.
- Targeting early stress tolerance pathways may enhance the efficacy of MAPK inhibitors for more durable cancer treatment.
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