BRAF activating mutations occur in approximately 10% of metastatic colorectal cancer (CRCs) and are associated with worse prognosis due to an inferior response to standard chemotherapy. Standard of care for patients with refractory metastatic BRAF V600E CRC is treatment with BRAF and EGFR inhibitors. However, responses are not durable. Lineage plasticity to neuroendocrine cancer is an emerging mechanism of targeted therapy resistance in several cancer types. Enteroendocrine cells (EECs), the neuroendocrine cell of the intestine, are uniquely present in BRAF V600E CRC as compared to BRAF wildtype CRC. Here, we demonstrated that combined BRAF and EGFR inhibition enriches for EECs in several models of BRAF V600E CRC. Additionally, EECs and other secretory cell types were enriched in a subset of BRAF V600E CRC patient samples following targeted therapy. Importantly, inhibition of the lysine demethylase LSD1 with a clinically relevant inhibitor attenuated targeted therapy-induced EEC enrichment through blocking the interaction of LSD1, CoREST2 and STAT3.
Statement of significance: Our findings that BRAF plus EGFR inhibition induces lineage plasticity in BRAF V600E CRC represents a new paradigm for how resistance to BRAF plus EGFR inhibition occurs and our finding that LSD1 inhibition blocks lineage plasticity has the potential to improve responses to BRAF plus EGFR inhibitor therapy in patients.