Prevalence and role of HER2 mutations in cancer

Abstract

HER2 activating mutations act as oncogenic drivers in various cancer types. In the clinic, they can be identified by next generation sequencing (NGS) in either tumor biopsies or circulating cell-free DNA (cfDNA). Preclinical data indicate that HER2 "hot spot" mutations are constitutively active, have transforming capacity in vitro and in vivo and show variable sensitivity to anti-HER2 based therapies. Recent clinical trials also revealed activity of HER2-targeted drugs against a variety of tumors harboring HER2 mutations. Here, we review the prevalence and type of HER2 mutations identified in different human cancers, their biochemical and biological characterization, and their sensitivity to anti HER2-based therapies in both preclinical and clinical settings.

Keywords: Afatinib; HER2 mutations; Neratinib; Next-generation sequencing (NGS); TCGA.

Conflict of interest statement

Conflict of Interest Statement:

M.S. is in the Advisory Board of Bioscience Institute and Menarini Ricerche, received research funds from Puma Biotechnology, Daiichi-Sankio, Targimmune, Immunomedics and Menarini Ricerche, is a co-founder of Medendi Medical Travel and in the past two years he received honoraria from Menarini Ricerche and ADC Pharma. ADS has received research funds from Merck, Genentech/Roche, Puma Biotechnology, Gilead Science and Immunomedics Inc.

Copyright © 2019 Elsevier Inc. All rights reserved.

Figures

Figure 1.. Timeline of key advances relating to the biology and therapeutic targeting of HER2 signaling.

Milestone discoveries that are relevant to HER2 amplified/overexpressing (boxes above the timeline arrow) and HER2 mutant tumors (boxes below the timeline arrow). Key events relating to the following fields of study are color coded as follows: FDA approval of anti-HER2 drugs (green); identification of HER2 mutation in cancers (yellow); clinical trial enrolling HER2 mutated cancers (blue).

Figure 2.. Distribution and frequency of HER2 mutations in solid tumors.

A: HER2 mutations identified across multiple cancer histologies. Only published studies on solid tumors with more than 100 samples were included. The frequency of HER2 mutations varies from 1% in cancer types such as melanoma and up to 12% in bladder cancer. Similar histologies are depicted with the same colors. B: Lollipop diagram depicting activating HER2 mutations identified in several cancer types. The most prevalent mutation, S310F/Y, is localized in the ECD and has been frequently reported in bladder, uterine cervix, breast and stomach cancer. HER2 mutations that mapped in the KD are also depicted. These are frequently found in lung, colorectal, breast and uterine tumors. Mutations in the TM and the JM domains recently identified in lung and colorectal cancer are also indicated. The most common mutated residues in the ECD, the JM and the KD modelled using PyMOL molecular visualization software are presented.

Figure 3.. Sensitivity of HER2 mutants to anti-HER2 therapy.

A heat map of the half maximal inhibitory concentration (IC50) values for different pan-ERBB inhibitors is shown. These drugs have different levels of activity against mutant HER2 proteins in vitro (box colors indicate the range of sensitivity/resistance for each mutant). The symbols in each box indicate the clinical results obtained from case reports or clinical trials. (C: clinical response; R: clinical resistance). Of note, some mutants that have been described to be sensitive to specific inhibitors in preclinical analyses were instead found to be resistance to the same drugs in patients.

Figure 4.. Model of HER2 dependent ER regulation.

Proposed model of regulation of ER activity by HER2 signaling in HER2 mutant ER+ breast tumors. In the absence of HER2 inhibition, active HER2 signaling results in suppression of ER dependent transcription. Inhibition of HER2 (with Neratinib or antibody-drug-conjugates such as TDM-1 or DS-8201) promotes increased ER activity as a result of an adaptive mechanism of cellular defense. The activation of ER-dependent transcription may be prevented through dual HER2/ER inhibition (Neratinib plus Fulvestrant or TDM-1/DS-8201 plus Fulvestrant).