Blockade of tumor cell-intrinsic PD-L1 signaling enhances AURKA-targeted therapy in triple negative breast cancer.

Autor:	Takchi A; Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN, United States., Zhang M; Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN, United States., Jalalirad M; Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN, United States., Ferre RL; Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN, United States., Shrestha R; Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN, United States., Haddad T; Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN, United States., Sarkaria J; Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN, United States., Tuma A; Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN, United States., Carter J; Department of Pathology, Mayo Clinic College of Medicine, Rochester, MN, United States., David H; Department of Pathology, Mayo Clinic College of Medicine, Rochester, MN, United States., Giridhar K; Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN, United States., Wang L; Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN, United States., Lange C; Department of Pharmacology, University of Minnesota, Minneapolis, MN, United States., Lendahl U; Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden., Ingle J; Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN, United States., Goetz M; Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN, United States., D'Assoro AB; Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in oncology [Front Oncol] 2024 May 30; Vol. 14, pp. 1384277. Date of Electronic Publication: 2024 May 30 (Print Publication: 2024).
DOI:	10.3389/fonc.2024.1384277
Abstrakt:	Triple negative breast cancer (TNBC) accounts for 15-20% of all breast cancers and mainly affects pre-menopausal and minority women. Because of the lack of ER, PR or HER2 expression in TNBC, there are limited options for tailored therapies. While TNBCs respond initially to standard of care chemotherapy, tumor recurrence commonly occurs within 1 to 3 years post-chemotherapy and is associated with early organ metastasis and a high incidence of mortality. One of the major mechanisms responsible for drug resistance and emergence of organ metastasis is activation of epithelial to mesenchymal transition (EMT) reprogramming. EMT-mediated cancer cell plasticity also promotes the enrichment of cancer cells with a CD44 high /CD24 low and/or ALDH high cancer stem-like phenotype [cancer stem cells (CSCs)], characterized by an increased capacity for tumor self-renewal, intrinsic drug resistance, immune evasion and metastasis. In this study we demonstrate for the first time a positive feedback loop between AURKA and intra-tumoral PD-L1 oncogenic pathways in TNBC. Genetic targeting of intra-tumoral PD-L1 expression impairs the enrichment of ALDH high CSCs and enhances the therapeutic efficacy of AURKA-targeted therapy. Moreover, dual AURKA and PD-L1 pharmacological blockade resulted in the strongest inhibition of tumor growth and organ metastatic burden. Taken together, our findings provide a compelling preclinical rationale for the development of novel combinatorial therapeutic strategies aimed to inhibit cancer cell plasticity, immune evasion capacity and organ metastasis in patients with advanced TNBC. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. (Copyright © 2024 Takchi, Zhang, Jalalirad, Ferre, Shrestha, Haddad, Sarkaria, Tuma, Carter, David, Giridhar, Wang, Lange, Lendahl, Ingle, Goetz and D’Assoro.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu