Epigenetic EGFR 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 neuroendocrinespecific 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.

The molecular characteristics of high-grade gastroenteropancreatic neuroendocrine neoplasms

“…Until recently, only small series have reported TP53 and RB1 alterations in GEP-NEC, and reports are methodologically inconsistent as some studies report gene mutations, others genetic alterations in general and some altered protein levels by immunohistochemistry. TP53 mutations in GEP-NEC are found in 57–59% ( Vijayvergia et al 2016 , Busico et al 2020 ), in colorectal NEC in 50–84% ( Shamir et al 2019 , Capdevila et al 2020 ) and in 8/12 pancreatic NEC ( Konukiewitz et al 2018 ). We found TP53 mutations in 64% of GEP-NEC, 68% in large-cell and 58% in small-cell, which are substantially fewer than observed in SCLC.…”

Extrapulmonary poorly differentiated NECs, including molecular and immune aspects

“…Urinary BRAF V600E circulating tumour DNA monitoring correlated with disease response, and it was concluded that BRAF V600E may be an oncogenic driver responsive to BRAF-MEK combination therapy in this disease site (Klempner et al 2016). Capdevila et al have recently reported that NEC from the colon and colorectal carcinomas are similar in their mutational repertoire, with NEC from the colon being particularly enriched in BRAF V600E mutations (Capdevila et al 2020). They concluded that BRAF V600E mutant colon NEC may benefit from BRAF inhibition in monotherapy, or with the addition of anti-EGF receptor (EGFR) antibodies, instead of MEK inhibitors for efficient blockade of acquired resistance (Capdevila et al 2020).…”

“…Capdevila et al have recently reported that NEC from the colon and colorectal carcinomas are similar in their mutational repertoire, with NEC from the colon being particularly enriched in BRAF V600E mutations (Capdevila et al 2020). They concluded that BRAF V600E mutant colon NEC may benefit from BRAF inhibition in monotherapy, or with the addition of anti-EGF receptor (EGFR) antibodies, instead of MEK inhibitors for efficient blockade of acquired resistance (Capdevila et al 2020).…”

Chemotherapy in NEN: still has a role?

“…Large, well designed prospective clinical trials shall be encouraged to generate good quality data that is particularly needed in this clinical setting. Moreover, personalized treatment options shall be further explored in certain molecular subgroups, such as NECs harboring BRAF mutations, ALK, ROS1 or NTRK traslocations, high TMB or MSI [124][125][126]. Indeed, there are several drugs currently approved for molecularly-defined, tumor-agnostic indications, such as the immune check-point inhibitor pembrolizumab for the treatment of high TMB or MSI tumors, or the NTRK inhibitors larotrectinib or entrectinib for tumors harboring NTRK, ALK or ROS1 traslocations [127][128][129][130].…”