Combined CDK4/6 and PI3Kα Inhibition Is Synergistic and Immunogenic in Triple-Negative Breast Cancer

Zhi Ling Teo; Stephanie Versaci; Sathana Dushyanthen; Franco Caramia; Peter Savas; Chris P Mintoff; Magnus Zethoven; Balaji Virassamy; Stephen J Luen; Grant A McArthur; Wayne A Phillips; Phillip K Darcy; Sherene Loi

doi:10.1158/0008-5472.CAN-17-2210

Combined CDK4/6 and PI3Kα Inhibition Is Synergistic and Immunogenic in Triple-Negative Breast Cancer

Cancer Res. 2017 Nov 15;77(22):6340-6352. doi: 10.1158/0008-5472.CAN-17-2210. Epub 2017 Sep 25.

Authors

Zhi Ling Teo^{1

2}, Stephanie Versaci¹, Sathana Dushyanthen¹, Franco Caramia¹, Peter Savas¹, Chris P Mintoff¹, Magnus Zethoven¹, Balaji Virassamy¹, Stephen J Luen¹, Grant A McArthur^{1

2}, Wayne A Phillips^{1

2

3

4}, Phillip K Darcy^{1

2

5}, Sherene Loi^{6

2}

Affiliations

¹ Division of Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
² Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia.
³ Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
⁴ Department of Surgery, St. Vincent's Hospital, University of Melbourne, Melbourne, Victoria, Australia.
⁵ Cancer Immunology Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
⁶ Division of Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. [email protected].

PMID: 28947417
DOI: 10.1158/0008-5472.CAN-17-2210

Abstract

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 RB1-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 in vivo 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. Cancer Res; 77(22); 6340-52. ©2017 AACR.

MeSH terms

Aminopyridines / administration & dosage
Aminopyridines / pharmacology
Animals
Antineoplastic Combined Chemotherapy Protocols / pharmacology
Cell Line, Tumor
Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors
Class I Phosphatidylinositol 3-Kinases / metabolism*
Cyclin-Dependent Kinase 4 / antagonists & inhibitors
Cyclin-Dependent Kinase 4 / metabolism*
Cyclin-Dependent Kinase 6 / antagonists & inhibitors
Cyclin-Dependent Kinase 6 / metabolism*
Drug Synergism
Female
Humans
Mammary Neoplasms, Experimental / drug therapy
Mammary Neoplasms, Experimental / enzymology
Mammary Neoplasms, Experimental / immunology
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, Knockout
Mice, SCID
Piperazines / administration & dosage
Piperazines / pharmacology
Purines / administration & dosage
Purines / pharmacology
Pyridines / administration & dosage
Pyridines / pharmacology
Survival Analysis
Thiazoles / administration & dosage
Thiazoles / pharmacology
Triple Negative Breast Neoplasms / drug therapy
Triple Negative Breast Neoplasms / enzymology*
Triple Negative Breast Neoplasms / immunology
Xenograft Model Antitumor Assays

Substances

Aminopyridines
Piperazines
Purines
Pyridines
Thiazoles
Alpelisib
Class I Phosphatidylinositol 3-Kinases
PIK3CA protein, human
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase 6
palbociclib
ribociclib