DNA Sequencing of Small Bowel Adenocarcinomas Identifies Targetable Recurrent Mutations in the ERBB2 Signaling Pathway.

Abstract

Little is known about the genetic alterations characteristic of small bowel adenocarcinoma (SBA). Our purpose was to identify targetable alterations and develop experimental models of this disease.<b>Experimental Design:</b> Whole-exome sequencing (WES) was completed on 17 SBA patient samples and targeted-exome sequencing (TES) on 27 samples to confirm relevant driver mutations. Two SBA models with <i>ERBB2</i> kinase activating mutations were tested for sensitivity to anti-ERBB2 agents <i>in vivo</i> and <i>in vitro</i>. Biochemical changes were measured by reverse-phase protein arrays. WES identified somatic mutations in 4 canonical pathways (WNT, ERBB2, STAT3, and chromatin remodeling), which were validated in the TES cohort. Although <i>APC</i> mutations were present in only 23% of samples, additional WNT-related alterations were seen in 12%. <i>ERBB2</i> mutations and amplifications were present in 23% of samples. Patients with alterations in the ERBB2 signaling cascade (64%) demonstrated worse clinical outcomes (median survival 70.3 months vs. 109 months; log-rank HR = 2.4, <i>P</i> = 0.03). Two ERBB2-mutated (V842I and Y803H) cell lines were generated from SBA patient samples. Both demonstrated high sensitivity to ERBB2 inhibitor dacomitinib (IC₅₀ < 2.5 nmol/L). In xenografts derived from these samples, treatment with dacomitinib reduced tumor growth by 39% and 59%, respectively, whereas it had no effect in an SBA wild-type <i>ERBB2</i> model. The <i>in vitro</i> and <i>in vivo</i> models of SBA developed here provide a valuable resource for understanding targetable mutations in this disease. Our findings support clinical efforts to target activating <i>ERBB2</i> mutations in patients with SBA that harbor these alterations.