HER3 Alterations in Cancer and Potential Clinical Implications

Abstract

In recent years, the third member of the HER family, kinase impaired HER3, has become a target of interest in cancer as there is accumulating evidence that HER3 plays a role in tumor growth and progression. This review focuses on HER3 activation in bladder, breast, colorectal, and lung cancer disease progression. HER3 mutations occur at a rate up to ~10% of tumors dependent on the tumor type. With patient tumors routinely sequenced for gene alterations in recent years, we have focused on HER3 mutations in bladder, breast, colon, and lung cancers particularly in response to targeted therapies and the potential to become a resistance mechanism. There are currently several HER3 targeting drugs in the pipeline, possibly improving outcomes for cancer patients with tumors containing HER3 activation and/or alterations.

Keywords: HER3; alteration; bladder cancer; breast cancer; colorectal cancer; lung cancer.

Figure 1

(a) HER3 dimerizes with other RTKs, most notably HER2, to activate downstream pathways involved in cell growth, survival, and signaling. (b) HER3 has several common mutations located across the four extracellular and kinase domains, as indicated by red stars. P: phosphorylation site, and NRG indicates the HER3 ligand neuregulin. Figure generated using BioRender.

Figure 2

The frequency of HER3 alterations as seen in bladder (n = 2419), breast (n = 8615), colorectal (n = 4453), and lung (n = 7204) cancers across different subtypes and multiple nonredundant studies. Figure rendered using cBioPortal [27,28].

Figure 3

The frequency of HER3 mutations in bladder cancer and their locations within the receptor. Figure rendered in cBioPortal using multiple studies (n = 2419). Gray indicates truncating mutation, green indicates a missense mutation, yellow indicates splice mutation, and brown indicates an in-frame mutation [27,28].

Figure 4

The frequency of HER3 mutations in breast cancer and their locations within the receptor. Figure rendered in cBioPortal using multiple studies (n = 8615). Gray indicates truncating mutation, green indicates a missense mutation, yellow indicates splice mutation, and brown indicates an in-frame mutation [27,28].

Figure 5

The frequency of HER3 mutations in colorectal cancer and their locations within the receptor. Figure rendered in cBioPortal using multiple studies (n = 4453). Gray indicates truncating mutation, green indicates a missense mutation, yellow indicates splice mutation, and brown indicates an in-frame mutation [27,28].

Figure 6

The frequency of HER3 mutations in lung cancer and their locations within the HER3 receptor. Figure rendered in cBioPortal using multiple studies (n = 7204). Gray indicates truncating mutation, green indicates a missense mutation, yellow indicates splice mutation, and brown indicates an in-frame mutation [27,28].

Figure 7

The main categories of HER3 targeting therapies include monoclonal antibodies, multitargeted antibodies, antibody-drug conjugates, and tyrosine kinase inhibitors (TKIs). Monoclonal antibodies bind to the extracellular domain of HER3. Multi-targeted antibodies include bispecific antibodies which combine two different antigen-binding sites in a single antibody. Antibody-Drug Conjugates are monoclonal antibodies chemically linked to a chemotherapeutic drug. Tyrosine kinase inhibitors are small molecules inhibitors that block tyrosine kinase activity. Figure generated using BioRender.