Abstract 1101: Functional genomics of HER2 and HER3 mutations and response to neratinib

Selective kinase inhibitors, such as erolotinib and lapatinib, and monoclonal antibodies, such as cetuximab, trastuzumab and pertuzumab, targeting EGFR and ERBB2 have elicited significant response rates in lung cancer patients harboring mutant EGFR alleles and breast cancer patients whose tumors harbor gene amplification of ERBB2. To date, only a small number of ERBB2 and ERBB3 mutations have been reported and biologically characterized. Moreover, the therapeutic impact of ERBB2 or ERBB3 mutant alleles and their value as an actionable target in patients has not been validated. While ERBB2 itself cannot bind ligand, it is a potent receptor that integrates growth signals via homo- or heterodimerization with other ERBB family members. Genomic alterations increase ERBB2 kinase activity by constitutively activating the kinase domain, enabling ligand-independent receptor activation, by promoting enhanced dimerization or other mechanisms that have yet to be elucidated. Although ERBB3 has limited inherent kinase activity and cannot homodimerize, ligand stimulation promotes dimerization with active kinases like ERBB2 and EGFR that can phosphorylate ERBB2 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 an analysis of ∼100 large-scale next generation sequencing datasets newly generated by our group (bladder), our institution (MSKCC-IMPACT), or found in recently published repositories (The Cancer Genome Atlas (TCGA), Broad, Genentech, Sanger, etc) to characterize the distribution and spectrum of mutations in the ERBB2 and ERBB3 genes. Data generated suggests that ERBB2 and ERBB3 mutations are highly prevalent in bladder cancer (each ∼10%), and recurrent, but with less frequency ( Citation Format: Aphrothiti J. Hanrahan, David M. Hyman, John Sfakianos, Alexis Jones, Ricardo Ramirez, Hannah Johnsen, Gopakumar Iyer, Hikmat A. Al-Ahmadie, Dean Bajorin, Bernard H. Bochner, Jonathan A. Coleman, Jonathan E. Rosenberg, Michael F. Berger, Sarat Chandarlapaty, Jose Baselga, David B. Solit. Functional genomics of HER2 and HER3 mutations and response to neratinib. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1101. doi:10.1158/1538-7445.AM2015-1101