Yuanhuacine Is a Potent and Selective Inhibitor of the Basal-Like 2 Subtype of Triple Negative Breast Cancer with Immunogenic Potential

SIMPLE SUMMARY: Most breast cancers express the estrogen, progesterone, and/or HER2 receptors and patients are treated with inhibitors targeting these receptors. Triple negative breast cancers (TNBCs) lack these receptors and thus patients with TNBC do not benefit from existing targeted therapies. There is a continued search for effective targets for the treatment of these heterogeneous tumors. We identified a class of plant-derived natural products, including yuanhuacine, that selectively kill cells that represent a molecularly defined subtype of TNBC. These compounds also promote expression of an immunological profile that is beneficial for engaging the immune system, which could provide an added benefit in TNBC. The mechanism of action of both the TNBC selectivity and immunological phenotypes is associated with activation of protein kinase C. Yuanhuacine has potent antitumor efficacy in a mouse model of TNBC, identifying a new therapeutic target for the treatment of this deadly disease. 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. Furthermore, 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.