Activating HER3 mutations in breast cancer

Abstract

Recent studies have highlighted a role of HER3 in ER and HER2-driven breast cancers. We sought to investigate the role of patient-derived HER3 mutations in ER+ and HER2+ breast cancer cells using ectopic expression of HER3 mutants. We found that HER3T355I mutant is activating with increased cell proliferation in ER+ T47D and MCF-7 breast cancer cells lacking HER2 over-expression. Immunoblotting and receptor tyrosine kinase array results indicated that T47D and MCF-7 cells expressing HER3T355I had increased p-HER4 and p-HER1 expression. Our data showed that HER3T355I induced cell proliferation is via HER4/HER1-dependent ERK1/2 and cyclinD1 mediated pathways in ER+ cells. ERα expression is upregulated in ER+ cells expressing HER3T355I mutant. We noted crosstalk between ERα and HER3 in T47D cells. Several HER3 mutants (F94L, G284R, D297Y, T355I, and E1261A) acquired a gain-of-function phenotype in MCF10AHER2 cells and were resistant to lapatinib. These mutants increased HER2-HER3 heterodimerization. Knocking down HER3 from ovarian and colorectal cancers with endogenous HER3 mutations abrogated cancer cell proliferation. Overall, this study provides the first systematic assessment of how mutations in HER3 affect response of ER+ and HER2+ breast cancers to clinically relevant inhibitors and finds that HER3 mutations can be activating independent of HER2 over-expression.

Complementary Sequential Circulating Tumor Cell (CTC) and Cell-Free Tumor DNA (ctDNA) Profiling Reveals Metastatic Heterogeneity and Genomic Changes in Lung Cancer and Breast Cancer

“…Indeed, the alterations found in these genes such as RYR2, NOTCH1 and DMBT1 have strong association with high tumor burden and tumorigenesis (44)(45)(46)(47), possibly resulting in a worse prognosis in lung cancer patients. Further, frequent alterations of USH2A, EGFR and ERBB3 were previously reported in association with cellular proliferation (48)(49)(50)(51). Further, we observed significant increase of copy number changes in the tumor and CTCs during disease progression.…”

Prospects for pharmacological targeting of pseudokinases

“…The mutations in the extracellular domain might destabilize its autoinhibited conformation, thereby favouring HER3 dimerization with other members of the HER family. Several of these mutations promote ligand-independent cell survival and tumour growth both in vitro and in vivo in a HER2-dependent manner 48,49 (Fig. 2a).…”

Prevalence and role of HER2 mutations in cancer

“…Moreover, among the 66 total patients of the SUMMIT trial that did not respond to Neratinib monotherapy, HER3 mutations were found in 14% of their tumors. Although additional studies are needed to evaluate whether these mutations can confer resistance to Neratinib, it has recently been demonstrated that breast cancer cell lines harboring HER3 mutations (F94L, G284R, D297Y, T355I, and E1261A) have enhanced HER2-HER3 heterodimerization that induces a gain-of-function phenotype and results in Lapatinib resistance (Mishra, et al, 2018). Furthermore, it has been recently demonstrated that the FDA-approved pan-ERBB inhibitors Afatinib and Neratinib effectively reduced the expression of mutant K-RAS proteins in several tumor types (Moll HP, et al, 2018) (Booth et al, 2018) (Booth et al, 2019), thus supporting the use of these agents to treat K-RAS mutated cancers.…”