HER3 missense mutations can inhibit response of tumor cells to HER2-targeted therapies.

  • Major Finding:HER3 missense mutations can inhibit response of tumor cells to HER2-targeted therapies.

  • Concept: PI3K inhibitors recover response to HER2-targeted therapies in cells with mutated HER2 and HER3.

  • Impact: Combined HER2 and PI3K inhibition may be a promising strategy in tumors with HER2 and HER3 mutations.

Activating mutations in the receptor tyrosine kinase gene HER2 occur in a subset of breast and other cancers and are key biomarkers for the treatment of these tumors. They are often found alongside missense mutations affecting the related receptor HER3, with which HER2 can heterodimerize, but little is known about how these HER3 mutations affect HER2 and the subsequent response to targeted therapies. Using computational modeling, Hanker, Brown, and colleagues predicted that the HER3E928G mutation would enhance kinase domain dimerization and increase HER2 activation compared with wild-type HER3. Co-immunoprecipitation experiments in cells engineered to express combinations of wild-type or mutant HER2 and HER3 revealed that the simultaneous presence of HER2 and HER3 mutants increased HER2/HER3 and PI3K activation in a ligand-independent manner. In vitro 3-D culture of nonmalignant breast epithelial cells transduced with combinations of HER2 and HER3 mutations showed increased invasion and growth compared with cells expressing only HER2 mutations. Cells expressing the HER2S310F mutant were sensitive to HER2-targeting antibody treatments that inhibited dimerization and blocked phosphorylation of HER3 as well as downstream phosphorylation of AKT and S6. The introduction of HER3E928G reversed this response. HER3 mutations influenced the response of HER2 wild-type and mutated cells and patient-derived organoids to the tyrosine kinase inhibitor neratinib, with simulations suggesting that the association of mutant HER3 with HER2 reduced the binding affinity of neratinib to HER2. Combining neratinib with the PI3K inhibitor alpelisib to treat cells expressing both HER2 and HER3 mutants blocked AKT and S6 phosphorylation more effectively than either single agent alone, also reducing growth and invasion in a 3-D culture model. RNAi knockdown experiments in colorectal cancer cells harboring somatic HER2 and HER3 mutations also showed that both regulate proliferation and PI3K activity, and that neratinib and alpelisib were required to block proliferation and growth of xenografts in vivo. The authors conclude that HER3 mutations affect response to single-agent HER2-targeting TKIs and suggest that combination therapy with PI3K inhibitors may be a promising therapeutic strategy.

Hanker AB, Brown BP, Meiler J, Marín A, Jayanthan HS, Ye D, et al. Co-occurring gain-of-function mutations in HER2 and HER3 modulate HER2/HER3 activation, oncogenesis, and HER2 inhibitor sensitivity. Cancer Cell 2021;39:1099–114.

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