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Nat Commun. 2019 Feb 6;10(1):620. doi: 10.1038/s41467-019-08541-2.

Pharmacological reactivation of MYC-dependent apoptosis induces susceptibility to anti-PD-1 immunotherapy.

Author information

1
Cancer Cell Circuitry Laboratory, Research Programs Unit/Translational Cancer Biology and Medicum, University of Helsinki, P.O. Box 63, Street address: Haartmaninkatu 8, 00014, Helsinki, Finland.
2
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 360 Longwood Ave, 02215, Boston, MA, USA.
3
Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Haartmaninkatu 8, 00290, Helsinki, Finland.
4
Research Programs Unit/Molecular Neurology, Biomedicum Stem Cell Center, University of Helsinki, Haartmaninkatu 8, 00290, Helsinki, Finland.
5
Leibniz Institute of Age Research, Fritz Lipmann Institute e.V, Beutenbergstraße 11, 07745, Jena, Germany.
6
Department of Biosciences and Institute of Biotechnology, University of Helsinki, Viikinkaari 5, 00790, Helsinki, Finland.
7
Oncotest GmbH, (Now part of Charles River Laboratories Inc, 251 Ballardvale St, Wilmington, MA 01887, USA), Freiburg, Germany.
8
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Tukholmankatu 3, 00290, Helsinki, Finland.
9
Department of Mathematics and Statistics, University of Turku, Vesilinnantie 5, 20500, Turku, Finland.
10
Research Programs Unit / Translational Cancer Biology & Medicum, University of Helsinki, P.O. Box 63 (Street address: Haartmaninkatu 8), 00290, Helsinki, Finland.
11
Department of Oncology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 4, 00290, Helsinki, Finland.
12
Department of Pathology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 3, 00290, Helsinki, Finland.
13
Breast Surgery Unit, Helsinki University Hospital, Kasarmikatu 11-13, 00290, Helsinki, Finland.
14
Department of Pathology, HUSLAB and Haartman Institute, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 3, 00290, Helsinki, Finland.
15
Theodor Boveri Institute and Comprehensive Cancer Center Mainfranken, Biocenter, University of Würzburg, Am Hubland, D-970074, Germany.
16
Oncology Development, AbbVie, Inc., 1 N Waukegan Road, North Chicago, IL, 60064, USA.
17
Cancer Cell Circuitry Laboratory, Research Programs Unit/Translational Cancer Biology and Medicum, University of Helsinki, P.O. Box 63, Street address: Haartmaninkatu 8, 00014, Helsinki, Finland. Juha.Klefstrom@helsinki.fi.

Abstract

Elevated MYC expression sensitizes tumor cells to apoptosis but the therapeutic potential of this mechanism remains unclear. We find, in a model of MYC-driven breast cancer, that pharmacological activation of AMPK strongly synergizes with BCL-2/BCL-XL inhibitors to activate apoptosis. We demonstrate the translational potential of an AMPK and BCL-2/BCL-XL co-targeting strategy in ex vivo and in vivo models of MYC-high breast cancer. Metformin combined with navitoclax or venetoclax efficiently inhibited tumor growth, conferred survival benefits and induced tumor infiltration by immune cells. However, withdrawal of the drugs allowed tumor re-growth with presentation of PD-1+/CD8+ T cell infiltrates, suggesting immune escape. A two-step treatment regimen, beginning with neoadjuvant metformin+venetoclax to induce apoptosis and followed by adjuvant metformin+venetoclax+anti-PD-1 treatment to overcome immune escape, led to durable antitumor responses even after drug withdrawal. We demonstrate that pharmacological reactivation of MYC-dependent apoptosis is a powerful antitumor strategy involving both tumor cell depletion and immunosurveillance.

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