Abstract PD3-05: Co-occurring gain-of-function mutations in HER2 and HER3 cooperate to enhance HER2/HER3 binding, HER-dependent signaling, and breast cancer growth

摘要: ERBB2, the gene encoding HER2, is mutated in 2-4% of breast cancers. The HER2 tyrosine kinase inhibitor neratinib has shown clinical activity against cancers harboring activating mutations, suggesting these tumors depend on signaling. Co-occurring and HER3 (ERBB3) mutations have been reported patients who respond to (Hanker et al., Cancer Discov. 2017) possibility cooperativity both oncogenes. Co-expression mutant intracellular domains HEK293 cells enhanced phosphorylation ERK compared expression either alone, which was blocked by 100 nM neratinib. Interrogation TCGA, METABRIC, Project GENIE, Foundation Medicine datasets revealed that gain-of-function ERBB2 ERBB3 co-occur with a statistically significant frequency. For example, (8.3% ERBB2-mutant vs 2.3% WT; q=1.37x10-10). We hypothesized co-occurring cooperate enhance signaling dependence cancer progression. Thirty-four unique were found harbor HER3, most common ERBB2L755S/ERBB3E928G (n=10), ERBB2V777L/ERBB3E928G(n=6), ERBB2L869R/Q/ERBB3E928G (n=4). Using co-immunoprecipitation assays antibodies transfected cells, we co-expression HER3E928G wild type (WT) or HER2L755S HER2L869R HER3WT, slightly increased HER2-HER3 dimerization. However, binding strongest between double mutants. This accompanied highest levels Y1289 p-HER3 expressing each HER2L755S, HER2V777L, respective WT heterodimer partner. Structural modeling HER2L869R/HER3E928G double-mutant predicted mutation, located at dimer interface, may heterodimerization through decreased bulk electrostatic repulsion. also noted mutation be close proximity ( MCF7 “knock-in” incorporating (or HER2WT) stably transduced HER3WT. mutants strongly estrogen-independent growth 3D Matrigel over alone. are currently testing inhibitors HER2/HER3 signaling, including ± trastuzumab, trastuzumab + pertuzumab, ERBB1-3 antibody mixture Sym013, determine therapeutic strategies block cooperative induced mutations. Conclusions: promotes HER2/HER binding, phosphorylation, tumor cell proliferation. aim identify vulnerabilities for Citation Format: Hanker AB, Koch JP, Ye D, Sliwoski G, Sheehan J, Kinch LN, Red Brewer M, He Miller VA, Lalani AS, Cutler, Jr. RE, Croessmann S, Zabransky DJ, Meiler Arteaga CL. HER-dependent [abstract]. In: Proceedings 2018 San Antonio Breast Symposium; Dec 4-8; Antonio, TX. Philadelphia (PA): AACR; Res 2019;79(4 Suppl):Abstract nr PD3-05.