Data from Computational and Functional Analyses of HER2 Mutations Reveal Allosteric Activation Mechanisms and Altered Pharmacologic Effects

• DOI: 10.1158/0008-5472.c.6626126.v1
• Publication Date: 2023-05-02T08:21:29Z
• Authors: Noboru Ishiyama; Matthew O'Connor; Andrei Salomatov; Darlene Romashko; Shalabh Thakur; Ahmet Mentes; Julia F. Hopkins; Garrett M. Frampton; Lee A. Albacker; Anna Kohlmann; Christopher Roberts; Elizabeth Buck

<div>Abstract<p>Amplification of HER2 can drive the proliferation cancer cells, and several inhibitors have been successfully developed. Recent advances in next-generation sequencing now reveal that <i>HER2</i> is subject to mutation, with over 2,000 unique variants observed human cancers. Several examples oncogenic mutations described, these primarily occur at allosteric sites outside ATP-binding site. To identify full spectrum driver aside from a few well-studied mutations, we developed mutation-allostery-pharmacology (MAP), an <i>in silico</i> prediction algorithm based on machine learning. By applying this computational approach 820 single-nucleotide variants, list 222 known potential was produced. Of 111 were screened by Ba/F3-retrovirus assays; 37 experimentally determined be comprising 15 previously characterized 22 newly identified mutations. These mostly affected extracellular domain (ECD), transmembrane domain, kinase HER2, only single mutation orthosteric ATP Covalent homodimerization established as common mechanism activation among ECD including most prevalent S310F. Furthermore, mutants enhanced covalent altered pharmacology reduces activity existing anti-HER2 agents, mAb trastuzumab tyrosine inhibitor lapatinib. Overall, MAP-scoring functional validation analyses provided new insights into therapeutic targeting cancer.</p>Significance:<p>This study share dimerization oncogenicity, suggesting need for novel treat HER2-mutant cancers.</p></div>