DNA Sequencing of Small Bowel Adenocarcinomas Identifies Targetable Recurrent Mutations in the ERBB2 Signaling Pathway
Type
ArticleAuthors
Adam, LianaSan Lucas, F Anthony
Fowler, Jerry
Yu, Yao
Wu, Wenhui
Liu, Yulun
Wang, Huamin
Menter, David G.
Tetzlaff, Michael T.
Ensor, Joe E
Manyam, Ganiraju
Arold, Stefan T.

Huff, Chad D
Kopetz, Scott
Scheet, Paul
Overman, Michael J
KAUST Department
Biological and Environmental Sciences and Engineering (BESE) DivisionBioscience Program
Computational Bioscience Research Center (CBRC)
Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division
Date
2019-01-15Permanent link to this record
http://hdl.handle.net/10754/630585
Metadata
Show full item recordAbstract
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. While 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 hazard ratio 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<2.5nM). In xenografts derived from these samples, treatment with dacomitinib reduced tumor growth by 39% and 59%, respectively, while 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 harbors these alterations.Citation
Adam L, San Lucas FA, Fowler J, Yu Y, Wu W, et al. (2018) DNA Sequencing of Small Bowel Adenocarcinomas Identifies Targetable Recurrent Mutations in the ERBB2 Signaling Pathway. Clinical Cancer Research: clincanres.1480.2018. Available: http://dx.doi.org/10.1158/1078-0432.ccr-18-1480.Sponsors
National Cancer Institute[P30CA16672]Journal
Clinical Cancer ResearchAdditional Links
http://clincancerres.aacrjournals.org/content/early/2018/10/23/1078-0432.CCR-18-1480ae974a485f413a2113503eed53cd6c53
10.1158/1078-0432.ccr-18-1480