Abstract
Human epidermal growth factor receptor (EGFR) 2 (HER2) is overexpressed/amplified in about 25% of all breast cancers, and EGFR is overexpressed in up to 76% and amplified in up to 24% of triple-negative breast cancers (TNBC). Here, we aimed to identify inhibitors that may enhance the anti-tumor activity of neratinib for HER2+ breast cancer and TNBC. By conducting a non-biased high-throughput RNA interference screening, we identified PI3K/AKT/mTOR and MAPK as two potential inhibitory synergistic canonical pathways. We confirmed that everolimus (mTOR inhibitor) and trametinib (MEK inhibitor) enhances combinatorial anti-proliferative effects with neratinib under anchorage-independent growth conditions (p < 0.05). Compared to single agent neratinib, the combination therapies significantly enhanced tumor growth inhibition in both SUM190 HER2+ breast cancer (neratinib plus everolimus, 77%; neratinib plus trametinib, 77%; p < 0.0001) and SUM149 TNBC (neratinib plus everolimus, 71%; neratinib plus trametinib, 81%; p < 0.0001) xenograft models. Compared to single-agent neratinib, everolimus, or trametinib, both everolimus plus neratinib and trametinib plus neratinib significantly suppressed proliferation marker Ki67 and enhanced antitumor efficacy by activating the apoptosis pathway shown by increased Bim and cleaved-PARP expression. Taken together, our data justify new neratinib-based combinations for both HER2+ breast cancer and TNBC.
Highlights
The ERBB receptor tyrosine kinase family consists of four receptors: epidermal growth factor receptor (EGFR), human EGFR 2 (HER2), HER3, and HER4, which activate oncogenic pathways by homo- or heterodimerization in many types of cancers
To the best of our knowledge, this present preclinical study is the first to show that neratinib can potentially induce tumor growth inhibition (TGI) in both HER2+ breast cancer and triple-negative breast cancers (TNBC) when cotreated with inhibitors of the PI3K/Akt-mTOR or MAPK pathway
We identified the PI3K and MAPK pathways as potential targets for combination with neratinib to enhance its anti-tumor effect
Summary
The ERBB receptor tyrosine kinase family consists of four receptors: epidermal growth factor receptor (EGFR), human EGFR 2 (HER2), HER3, and HER4, which activate oncogenic pathways by homo- or heterodimerization in many types of cancers. EGFR is overexpressed in up to 76% and amplified in up to 24% of triple-negative breast cancers (TNBC) cases [1,2]. Several EGFR-targeted antibodies (e.g., cetuximab and panitumumab) combined with chemotherapy have been tested in clinical trials, in which they have improved the survival of patients with TNBC [6,7]. HER2 and HER3 co-expression is associated with poor survival outcomes in patients with HER2+ breast cancer [9,10]. The co-existence of high levels of HER3 and EGFR is correlated with worse breast cancer-specific and distant metastasis-free survival for patients with TNBC [11]. In estrogen receptor-positive breast cancer, HER4 impairs the efficacy of tamoxifen and is associated with poor survival outcomes [12,13]
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