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• W4361946979 abstract "<div>AbstractPurpose:<p>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.</p><p><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.</p>Results:<p>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.</p>Conclusions:<p>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.</p></div>" @default.
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• W4361946979 date "2023-03-31" @default.
• W4361946979 modified "2023-10-15" @default.
• W4361946979 title "Data from DNA Sequencing of Small Bowel Adenocarcinomas Identifies Targetable Recurrent Mutations in the ERBB2 Signaling Pathway" @default.
• W4361946979 doi "https://doi.org/10.1158/1078-0432.c.6529001" @default.
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