Date Published: June 3, 2019
Publisher: Public Library of Science
Author(s): Amy Allen, Alice Can Ran Qin, Nitya Raj, Jiawan Wang, Sharmeen Uddin, Zhan Yao, Laura Tang, Paul A. Meyers, Barry S. Taylor, Michael F. Berger, Rona Yaeger, Diane Reidy-Lagunes, Christine A. Pratilas, Suzie Chen.
The clinical significance of BRAF alterations in well-differentiated (WD) metastatic pancreatic neuroendocrine tumor (panNET) is unknown, but BRAF-mutated panNET could represent a subset characterized by an identifiable and clinically actionable driver. Following the identification of two patients with WD metastatic panNET whose tumors harbored BRAF mutations, we queried the MSK-IMPACT series of 80 patients with WD metastatic panNET for additional mutations in BRAF, and in other genes involved in RAS/ RTK/ PI3K signaling pathways. BRAF mutations were identified in six samples (7.5%): two tumors harbored V600E mutations, one tumor each expressed K601E, T599K, and T310I mutations, and one tumor expressed both G596D and E451K BRAF. Few additional actionable driver alterations were identified. To determine the ERK activating capability of four BRAF mutations not previously characterized, mutant constructs were tested in model systems. Biochemical characterization of BRAF mutations revealed both high and low activity mutants. Engineered cells expressing BRAF K601E and V600E were used for in vitro drug testing of RAF and MEK inhibitors currently in clinical use. BRAF K601E demonstrated reduced sensitivity to dabrafenib compared to BRAF V600E, but the combination of RAF plus MEK inhibition was effective in cells expressing this mutation. Herein, we describe the clinical course of a patient with BRAF K601E and a patient with BRAF V600E WD metastatic panNET, and the identification of four mutations in BRAF not previously characterized. The combined clinical and biochemical data support a potential role for RAF and MEK inhibitors, or a combination of these, in a selected panNET population.
Pancreatic neuroendocrine tumors (panNET) are an uncommon and heterogeneous group of cancers, representing 1–2% of all cancers originating in the pancreas. While many of these tumors exhibit slow-growing and indolent behavior, most patients present with metastatic disease, and ultimately succumb to this cancer. Recent research efforts to understand the genomic landscape of this disease have identified changes in chromatin remodeling genes and in elements of the mTOR pathway in a subset of well-differentiated (WD) panNET, but few clinically actionable driver alterations [1, 2].
In our large series of WD metastatic panNET, we find that BRAF alterations are recurrent and potentially targetable. BRAF alterations included V600E and, in some cases, non-V600 activating mutations. Our analysis of signaling in cells with BRAF K601E mutation suggests that both tumors with V600E BRAF and tumors with some non-V600 activating BRAF mutations may be sensitive to combined RAF and MEK inhibition.