Acquired resistance of metastatic melanoma (MM) tumors to BRAF V600E inhibitors (BRAFis) is commonplace in the clinic. Habitual relapse of patients contributes to <20% 5-year survival rates in MM. We previously identified serine synthesis as a critical mechanism of late-stage cancer cell resistance to BRAFis. Pretreatment with DNA-damaging agent and nucleoside analog gemcitabine resensitized drug-resistant cancer cells to BRAFis dabrafenib (Tafinlar) and vemurafenib (Zelboraf). The combination treatments were effective against BRAF wild type cancer cells, potentially expanding the clinical reach of BRAFis. In this study, we identify two additional DNA-damaging agents that resensitized drug-resistant MM and pancreatic cancer cells to BRAFis dabrafenib and encorafenib. We identify the antifolate and DNA-damaging agent methotrexate (MTX), and the topoisomerase 1 inhibitor and DNA-damaging agent camptothecin (Camp) as sensitizers of late-stage, drug-resistant cancer cells to BRAFis dabrafenib and encorafenib (LGX818). Importantly, we show a novel positive correlation between DNA repair delay and and allosteric MAPK activation via BRAFi treatment in BRAF wild type cells. Cells arrest in G1/S following DNA-damaging agent + BRAFi combination treatments and ultimately, cell death is triggered via apoptosis, presumably due to DNA damage repair delays. Additionally, we have identified activating KRAS codon 12 mutations as critical to the efficacy of combination treatments. In summary, we have elucidated a novel method of cell death induction via DNA-damaging agent + BRAFi combination treatments that has the potential to significantly impact late-stage MM and pancreatic cancer therapy in the clinic.

Citation Format: Vikram Bhattacharjee. Killing late-stage cancer cells by coupling DNA damage induction with MAPK pathway activation [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A074.