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Diarrhea is one of the most commonly reported adverse effect of hemotherapy and targeted cancer therapies, such as tyrosine kinase inhibitors (TKI), which often significantly impact patient quality of life, morbidity, and mortality. Neratinib is an oral, irreversible pan‐HER tyrosine kinase inhibitor, which is clinically active in HER2‐positive breast cancer. Diarrhea is the most common side effect of this potent anticancer drug and the reasons for this adverse effect are still largely unclear. We have recently shown that activation of the calcium‐sensing Receptor (CaSR) can inhibit secretagogue‐induced diarrhea in the colon, therefore we hypothesized that CaSR activation may also mitigate neratinib‐induced diarrhea. Using an established ex vivo model of isolated intestinal segments, we investigated neratinib‐induced fluid secretion and the ability of CaSR activation to abate the secretion. In our study, individual segments of the rat intestine (proximal, middle, distal small intestine, and colon) were procured and perfused intraluminally with various concentrations of neratinib (10, 50, 100 nmol L−1). In a second set of comparison experiments, intraluminal calcium concentration was modulated (from 1.0 to 5.0 or 7.0 mmol L−1), both pre‐ and during neratinib exposure. In a separate series of experiments R‐568, a known calcimimetic was used CaSR activation and effect was compared to elevated Ca2+ concentration (5.0 and 7.0 mmol L−1). As a result, CaSR activation with elevated Ca2+ concentration (5.0 and 7.0 mmol L−1) or R‐568 markedly reduced neratinib‐induced fluid secretion in a dose‐dependent manner. Pre‐exposure to elevated luminal calcium solutions (5.0 and 7.0 mmol L−1) also prevented neratinib‐induced fluid secretion. In conclusion, exposure to luminal neratinib resulted in a pronounced elevation in fluid secretion in the rat intestine. Increasing luminal calcium inhibits the neratinib‐associated fluid secretion in a dose‐dependent manner. These results suggest that CaSR activation may be a potent therapeutic target to reduce chemotherapy‐associated diarrhea. [ABSTRACT FROM AUTHOR]

An estimated 15–20% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2/ERBB2/neu). Two small-molecule tyrosine kinase inhibitors (TKIs), lapatinib and neratinib, have been approved for the treatment of HER2-positive (HER2+) breast cancer. Lapatinib, a reversible epidermal growth factor receptor (EGFR/ERBB1/HER1) and HER2 TKI, is used for the treatment of advanced HER2+ breast cancer in combination with capecitabine, in combination with trastuzumab in patients with hormone receptor-negative metastatic breast cancer, and in combination with an aromatase inhibitor for the first-line treatment of HER2+ breast cancer. Neratinib, a next-generation, irreversible pan-HER TKI, is used in the US for extended adjuvant treatment of adult patients with early-stage HER2+ breast cancer following 1 year of trastuzumab. In Europe, neratinib is used in the extended adjuvant treatment of adult patients with early-stage hormone receptor-positive HER2+ breast cancer who are less than 1 year from the completion of prior adjuvant trastuzumab-based therapy. Preclinical studies have shown that these agents have distinct properties that may impact their clinical activity. This review describes the preclinical characterization of lapatinib and neratinib, with a focus on the differences between these two agents that may have implications for patient management. [ABSTRACT FROM AUTHOR]

Activating mutations in HER2 (ERBB2) drive the growth of a subset of breast and other cancers and tend to co-occur with HER3 (ERBB3) missense mutations. The HER2 tyrosine kinase inhibitor neratinib has shown clinical activity against HER2 -mutant tumors. To characterize the role of HER3 mutations in HER2- mutant tumors, we integrate computational structural modeling with biochemical and cell biological analyses. Computational modeling predicts that the frequent HER3E928G kinase domain mutation enhances the affinity of HER2/HER3 and reduces binding of HER2 to its inhibitor neratinib. Co-expression of mutant HER2/HER3 enhances HER2/HER3 co-immunoprecipitation and ligand-independent activation of HER2/HER3 and PI3K/AKT, resulting in enhanced growth, invasiveness, and resistance to HER2-targeted therapies, which can be reversed by combined treatment with PI3Kα inhibitors. Our results provide a mechanistic rationale for the evolutionary selection of co-occurring HER2/HER3 mutations and the recent clinical observations that HER3 mutations are associated with a poor response to neratinib in HER2- mutant cancers. [Display omitted] • Co-occurring HER2/HER3 mutations promote oncogenesis and invasion via PI3K activation • HER3 mutations reduce sensitivity to HER2 inhibitors in HER2- mutant cancer cells • Tumors with HER2/HER3 mutations are sensitive to HER2 TKI + PI3Kα inhibitor Hanker and Brown et al. demonstrate that co-occurring HER2 and HER3 mutations cooperatively activate HER2/HER3 and PI3K signaling in tumor cells, leading to enhanced growth, invasion, and resistance to HER2 inhibitors. HER2/HER3 double-mutant tumor models are sensitive to the combination of a HER2 TKI and a PI3Kα inhibitor. [ABSTRACT FROM AUTHOR]