Activating HER2 mutations as emerging targets in multiple solid cancers

Abstract

The epidermal growth factor receptor (EGFR) family of transmembrane receptor tyrosine kinases activates signalling pathways regulating cellular proliferation and survival. HER2 is a non-ligand-binding member of this family and exerts its activity through heterodimerisation with other EGFR family members. HER2 functional activation promotes oncogenesis, leading to the investigation of HER2-directed agents in cancers with HER2 alterations. This has been best characterised in the context of HER2 gene amplification in breast and gastro-oesophageal cancers, for which HER2-directed drugs form part of standard treatment regimens. More recently, somatic HER2 gene mutations have been detected in a range of human cancer types. Preclinical data suggest that functionally activating HER2 mutations may drive and maintain cancers in a manner analogous to HER2 gene amplification and that HER2 mutations may similarly confer sensitivity to HER2-directed drugs. Here, we critically review the emerging roles for HER2-directed drugs in HER2 mutant cancers. We review data from experimental models, where our knowledge of the underlying biology of HER2 mutational activation remains incomplete. We discuss clinical data from Phase I and II clinical trials which evaluate HER2-directed agents (tyrosine kinase inhibitors and antibody-based drugs) in several cancer types. We highlight the heterogeneity of HER2 mutations in human cancers, differences in the clinical efficacy of HER2-directed drugs between cancer types and possible mechanisms of primary and acquired resistance, in order to guide clinical practice and future drug development.

Keywords: activating mutations; cancer; her2; oncogene; treatment.

Figure 1

Plots derived from provisional TCGA data from sequencing and expression analyses of invasive breast carcinoma cases. (A) Plot demonstrating the relationship between HER2 mRNA levels (from RNA sequencing analysis) and HER2 copy number (from GISTIC analysis) for individual breast cancer cases, where sufficient data were available for analysis. Data were derived from, and plotted through, cbioportal.org. Blue dots represent individual HER2 wild-type cases, and orange dots represent individual HER2 mutant cases. (B) Plot demonstrating the relationship between HER2 protein levels (from reverse phase protein array analysis) and HER2 copy number (from GISTIC analysis) for individual breast cancer cases. Data were derived from, and plotted through, cbioportal.org. Blue dots represent individual HER2 wild-type cases, and orange dots represent individual HER2 mutant cases. GISTIC, Genomic Identification of Significant Targets in Cancer; TCGA, The Cancer Genome Atlas.

Figure 2

(A) Schematic diagrams demonstrating the HER2 mutational heterogeneity among and between cases of invasive breast cancer (n=963), bladder urothelial cancer (n=127), lung adenocarcinoma (n=230) and across cancer types (164 individual studies). Upward strokes depict the spatial location of mutations found in the HER2 gene (x axis), and the number of cases with mutations at each codon are shown by the length of the upstrokes (y axis). All data in this figure have been derived from TCGA data deposited in cbioportal.org. Green dots indicate missense mutations, brown dots indicate in-frame mutations, black dots indicate truncating mutations and other mutations are indicated by purple dots. (B) Kaplan-Meier graph showing the survival of patients in the provisional TCGA dataset of invasive breast carcinoma cases (derived from data deposited in cbioportal.org), stratified by HER2 mutational status. The median survival was 46.4 months for all HER2 mutant cases (n=20) and 46.4 months for HER2 mutant cases without copy number gains (n=11), compared with 129.6 months for HER2 wild-type cases (P=0.0056 for all HER2 mutants, and P=0.2218 for HER2 mutant cases without copy number gains, by log-rank (Mantel-Cox) test).  GFR, growth factor receptor; TMD, transmembrane domain.

Figure 3

Graph showing the annual registration count of trials where HER2-directed agents have been, or are being, tested in HER2 mutant cancers. Trials registered by 13 August 2017 on the US National Institutes of Health (NIH) trial registry were categorised according to year of registration and targeted cancer type. All trials have been included, including one trial withdrawn prior to enrolment and one trial terminated due to insufficient accrual. GFR, growth factor receptor; TMD, transmembrane domain.