Abstract 3419: Frequency and function of ERBB3 mutations in bladder cancer
Authors: Aphrothiti J. Hanrahan, John P. Sfakianos, Ricardo Ramirez, Phillip H. Kim, Gopa Iyer, Hikmat A. Al-Ahmadie, Sasinya N. Scott, Dean F. Bajorin, Bernard H. Bochner, Jonathan A. Coleman, Jonathan E. Rosenberg, Michael F. Berger, Sarat Chandarlapaty, David B. Solit
Journal: Cancer Research (2014)

Abstract Deregulation of the HER family of receptor tyrosine kinases has been widely implicated in cancer initiation and progression. Activating mutations or gene amplification of EGFR and ERBB2 (HER2) are frequently found in non-small cell lung, breast, colorectal, glioblastoma and head and neck cancers. However, little is known regarding the prevalence or functionality of genomic alterations in the ERBB3 (HER3) isoform. Although ERBB3 has limited inherent kinase activity, ligand stimulation promotes its dimerization with active kinases like ERBB2 and EGFR that can phosphorylate ERBB3 which then promotes transformation. Thus genomic alterations in ERBB3 may be a key means of promoting oncogenic signaling despite the protein lacking robust enzymatic activity. We performed a meta-analysis of 40 cross-cancer next generation sequencing and copy number genomics data sets newly generated by our group (bladder) or found in recently published repositories (The Cancer Genome Atlas (TCGA), Broad, Genentech, Sanger, etc). Analogous to the singular 2013 publication on ERBB3 mutations to date, we found frequent mutations in ERBB3 in gastric tumors (∼11%). Preliminary analysis of our novel and expanding cohort of 109 high-grade bladder cancer tumors suggests that ERBB3 mutations are equally frequent in bladder cancer (∼10-12%). Collectively, EGFR, ERBB2 and ERBB3 alterations were found in 23-30% of all high-grade bladder cancers, typically in a mutually exclusive pattern suggesting that these may be driver events. ERBB3 mutations were distributed across all structural domains of the protein. We identified more than 15 novel ERBB3 mutations in our bladder cohort, including hotspot mutations in the extracellular domain (V104L/M, D297Y, others) that were recurrent across multiple cancers types. Stable retroviral overexpression of ERBB3 mutants into NIH-3T3 cells induced phosphorylation of ERBB3, activation of downstream signaling cascades and soft agar colony formation, all which were enhanced in the presence of neuregulin and inhibited by the dual EGFR/ERBB2 kinase inhibitor, neratinib, and a monoclonal antibody to ERBB3, AMG-888/U3-1287. These data highlight a large cohort of bladder cancer patients with novel, activating mutations in the tractable kinase ERBB3, that could potentially benefit from approved EGFR/ERBB2 targeted therapeutics in the clinic and novel ERBB3 therapeutics in early clinical trials. Citation Format: Aphrothiti J. Hanrahan, John P. Sfakianos, Ricardo Ramirez, Phillip H. Kim, Gopa Iyer, Hikmat A. Al-Ahmadie, Sasinya N. Scott, Dean F. Bajorin, Bernard H. Bochner, Jonathan A. Coleman, Jonathan E. Rosenberg, Michael F. Berger, Sarat Chandarlapaty, David B. Solit. Frequency and function of ERBB3 mutations in bladder cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3419. doi:10.1158/1538-7445.AM2014-3419