Abstract 1101: Functional genomics of HER2 and HER3 mutations and response to neratinib
Authors: Hanrahan Aphrothiti J. , Hyman David M. , Sfakianos John , Jones Alexis , Ramirez Ricardo , Johnsen Hannah , Iyer Gopakumar , Al-Ahmadie Hikmat A. , Bajorin Dean , Bochner Bernard H. , Coleman Jonathan A. , Rosenberg Jonathan E. , Berger Michael F. , Chandarlapaty Sarat , Baselga Jose , Solit David B. 
Published: August 2015

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 (&lt;5%), in stomach, breast, colon and lung cancers. Hotspots include mutation of S310F and a cluster of residues in the kinase domain in ERBB2 and the V104M mutation in ERBB3. Preliminary analysis of ∼300 tumors demonstrated that ERBB2 and ERBB3 mutations present in a typically in a mutually exclusive pattern suggesting that these may be driver events with overlapping biologic effects. Generation and expression of several of these ERBB2 and ERBB3 mutants induced receptor activation, cell transformation and tumor growth in isogenic cell line and xenograft models. Treatment with the dual EGFR/HER2 inhibitor, neratinib, in isogenic cell lines abrogated colony formation in soft agar and receptor activation and downstream signaling. We hope to correlate the in vitro potency of specific ERBB2 and ERBB3 mutations with drug response in patients on ongoing or future clinical trials of targeted ERBB therapies and determine the whether lineage, subclonality and co-altered genes, if present, predict for drug resistance.

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