Pi3k and mapk pathways as targets for combination with the pan-her irreversible inhibitor neratinib in her2-positive breast cancer and tnbc by kinome rnai screening

Jangsoon Lee, Huey Liu, Troy Pearson, Toshiaki Iwase, Jon Fuson, Alshad S. Lalani, Lisa D. Eli, Irmina Diala, Debu Tripathy, Bora Lim, Naoto T. Ueno

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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.

Original languageEnglish (US)
Article number740
JournalBiomedicines
Volume9
Issue number7
DOIs
StatePublished - Jul 2021

Keywords

  • HER2-positive breast cancer
  • Neratinib
  • RNAi screening
  • Synergistic effect
  • Triple-negative breast cancer

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • General Biochemistry, Genetics and Molecular Biology

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