Yuanhuacine is a potent and selective inhibitor of the basal-like 2 subtype of triple negative breast cancer with immunogenic potential

Charles S. Fermaintt, Thilini Peramuna, Shengxin Cai, Leila Takahashi-Ruiz, Jacob Nathaniel Essif, Corena V. Grant, Barry R. O’keefe, Susan L. Mooberry, Robert H. Cichewicz, April L. Risinger

Research output: Contribution to journalArticlepeer-review

Abstract

The heterogeneity of triple negative breast cancer (TNBC) has led to efforts to further subtype this disease with the hope of identifying new molecular liabilities and drug targets. Further-more, the finding that TNBC is the most inherently immunogenic type of breast cancer provides the potential for effective treatment with immune checkpoint inhibitors and immune adjuvants. Thus, we devised a dual screen to identify compounds from natural product extracts with TNBC subtype selectivity that also promote the expression of cytokines associated with antitumor immunity. These efforts led to the identification of yuanhuacine (1) as a potent and highly selective inhibitor of the basal-like 2 (BL2) subtype of TNBC that also promoted an antitumor associated cytokine signature in immune cells. The mechanism of action of yuanhuacine for both phenotypes depends on activation of protein kinase C (PKC), defining a novel target for the treatment of this clinical TNBC subtype. Yuanhuacine showed potent antitumor efficacy in animals bearing BL2 tumors further demonstrating that PKC could function as a potential pharmacological target for the treatment of the BL2 subtype of TNBC.

Original languageEnglish (US)
Article number2834
JournalCancers
Volume13
Issue number11
DOIs
StatePublished - Jun 1 2021

Keywords

  • Basal like 2
  • Daphnane type diterpenoids
  • Immunotherapy
  • Natural products
  • Pharmacology
  • Protein kinase C
  • Targeted therapy
  • Traditional Chinese herbal medicine
  • Triple negative breast cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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