Epigenetic <i>EGFR</i> Gene Repression Confers Sensitivity to Therapeutic BRAFV600E Blockade in Colon Neuroendocrine Carcinomas

Abstract Purpose: The limited knowledge of the molecular alterations that characterize poorly differentiated neuroendocrine carcinomas has limited the clinical development of targeted agents directed to driver mutations. Here we aim to identify new molecular targets in colon neuroendocrine carcinomas (co-NEC) and proof the efficacy of matching drugs. Experimental Design: We performed a multi-omic analysis of co-NEC to identify genetic or epigenetic alterations that could be exploited as effective drug targets. We compared co-NEC samples with colorectal carcinomas (CRC) to identify neuroendocrine-specific traits. Patients with co-NEC and patient-derived xenografts were treated with a BRAFV600E-blocking drug to demonstrate sensitivity. Results: co-NEC and CRC are similar in their mutational repertoire, although co-NECs are particularly enriched in BRAFV600E mutations. We report for the first time that V600EBRAF-mutant co-NECs may benefit from BRAF inhibition in monotherapy and how EGFR status is essential to predict innate sensitivity and acquired resistance by a differential methylation of its gene regulatory regions. Conclusions: The identification of V600E BRAF mutations in high-grade co-NECs has allowed the description of radiological responses to combination therapy of BRAF and MEK inhibitors in basket clinical trials. However, the molecular rationale for this treatment combination was based on the presence of the BRAF mutation and the efficacy observed in other cancer types such as melanoma. Future drug development in this setting should test BRAF inhibitors upfront and the addition of anti-EGFR antibodies instead of MEK inhibitors for an efficient blockade of acquired resistance.