Combined CDK4/6 and PI3Kα Inhibition Is Synergistic and Immunogenic in Triple-Negative Breast Cancer
2017
Details
- Autor(en) / Beteiligte
- Titel
- Combined CDK4/6 and PI3Kα Inhibition Is Synergistic and Immunogenic in Triple-Negative Breast Cancer
- Ist Teil von
- Cancer research (Chicago, Ill.), 2017-11, Vol.77 (22), p.6340-6352
- Ort / Verlag
- United States: American Association for Cancer Research, Inc
- Erscheinungsjahr
- 2017
- Link zum Volltext
- Quelle
- Electronic Journals Library
- Beschreibungen/Notizen
- New treatments for triple-negative breast cancer (TNBC) are urgently needed. Despite there being little evidence of clinical activity as single-agent therapies, we show that dual blockade of PI3Kα and CDK4/6 is synergistically effective against multiple -wild-type TNBC models. Combined PI3Kα and CDK4/6 inhibition significantly increased apoptosis, cell-cycle arrest, and tumor immunogenicity and generated immunogenic cell death in human TNBC cell lines. Combination treatment also significantly improved disease control in human xenograft models compared with either monotherapy. Combined PI3Kα and CDK4/6 inhibition significantly increased tumor-infiltrating T-cell activation and cytotoxicity and decreased the frequency of immunosuppressive myeloid-derived suppressor cells in a syngeneic TNBC mouse model. Notably, combined PI3Kα and CDK4/6 inhibition, along with inhibition of immune checkpoints PD-1 and CTLA-4, induced complete and durable regressions (>1 year) of established TNBC tumors Overall, our results illustrate convergent mechanisms of PI3Kα and CDK4/6 blockade on cell-cycle progression, DNA damage response, and immune-modulation and may provide a novel therapeutic approach for TNBC. .
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0008-5472eISSN: 1538-7445DOI: 10.1158/0008-5472.CAN-17-2210Titel-ID: cdi_proquest_miscellaneous_1943287833
- Format
- –
- Schlagworte
- Aminopyridines - administration & dosage, Aminopyridines - pharmacology, Animal models, Animals, Antineoplastic Combined Chemotherapy Protocols - pharmacology, Antitumor activity, Apoptosis, Breast cancer, Cancer, Cell activation, Cell death, Cell Line, Tumor, Class I Phosphatidylinositol 3-Kinases - antagonists & inhibitors, Class I Phosphatidylinositol 3-Kinases - metabolism, CTLA-4 protein, Cyclin-dependent kinase 4, Cyclin-Dependent Kinase 4 - antagonists & inhibitors, Cyclin-Dependent Kinase 4 - metabolism, Cyclin-Dependent Kinase 6 - antagonists & inhibitors, Cyclin-Dependent Kinase 6 - metabolism, Cytotoxicity, Deoxyribonucleic acid, Disease control, DNA, DNA damage, Drug Synergism, Female, Humans, Immune checkpoint, Immunogenicity, Immunomodulation, Immunosuppression, Inhibition, Lymphocytes T, Mammary Neoplasms, Experimental - drug therapy, Mammary Neoplasms, Experimental - enzymology, Mammary Neoplasms, Experimental - immunology, Medical treatment, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, PD-1 protein, Piperazines - administration & dosage, Piperazines - pharmacology, Purines - administration & dosage, Purines - pharmacology, Pyridines - administration & dosage, Pyridines - pharmacology, Suppressor cells, Survival Analysis, Thiazoles - administration & dosage, Thiazoles - pharmacology, Triple Negative Breast Neoplasms - drug therapy, Triple Negative Breast Neoplasms - enzymology, Triple Negative Breast Neoplasms - immunology, Tumors, Xenograft Model Antitumor Assays, Xenografts