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

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...

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Bibliographic Details
Published in:Cancers 2021-06, Vol.13 (11), p.2834
Main Authors: Fermaintt, Charles S., Peramuna, Thilini, Cai, Shengxin, Takahashi-Ruiz, Leila, Essif, Jacob Nathaniel, Grant, Corena V., O’Keefe, Barry R., Mooberry, Susan L., Cichewicz, Robert H., Risinger, April L.
Format: Article
Language:English
Subjects:
Adjuvants
Antitumor activity
Breast cancer
Cancer therapies
Chromatography
Cytokines
ErbB-2 protein
Experiments
Gene expression
Immune checkpoint inhibitors
Immune system
Immunogenicity
Kinases
Natural products
Patients
Phenotypes
Plants
Progesterone
Protein kinase C
Regression analysis
Therapeutic targets
Tumors
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Summary: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.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers13112834