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


ABSTRACT: PURPOSE: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.Experimental Design: 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 ERBB2 kinase activating mutations were tested for sensitivity to anti-ERBB2 agents in vivo and in vitro. Biochemical changes were measured by reverse-phase protein arrays. RESULTS:WES identified somatic mutations in 4 canonical pathways (WNT, ERBB2, STAT3, and chromatin remodeling), which were validated in the TES cohort. Although APC mutations were present in only 23% of samples, additional WNT-related alterations were seen in 12%. ERBB2 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, P = 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 ERBB2 model. CONCLUSIONS:The in vitro and in vivo models of SBA developed here provide a valuable resource for understanding targetable mutations in this disease. Our findings support clinical efforts to target activating ERBB2 mutations in patients with SBA that harbor these alterations.

SUBMITTER: Adam L 

PROVIDER: S-EPMC6335167 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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

Adam Liana L   San Lucas F Anthony FA   Fowler Richard R   Yu Yao Y   Wu Wenhui W   Liu Yulun Y   Wang Huamin H   Menter David D   Tetzlaff Michael T MT   Ensor Joe J   Manyam Ganiraju G   Arold Stefan T ST   Huff Chad C   Kopetz Scott S   Scheet Paul P   Overman Michael J MJ  

Clinical cancer research : an official journal of the American Association for Cancer Research 20181023 2


<h4>Purpose</h4>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  ...[more]

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