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

Heidi M. Haikala, Johanna M. Anttila, Elsa Marques, Tiina Raatikainen, Mette Ilander, Henna Hakanen, Hanna Ala-Hongisto, Mariel Savelius, Diego Balboa, Bjoern Eyss, Vilja Eskelinen, Pauliina Munne, Anni I. Nieminen, Timo Otonkoski, Julia Schüler, Teemu D. Laajala, Tero Aittokallio, Harri Sihto, Johanna Mattson, Päivi Heikkilä, Marjut Leidenius, Heikki Joensuu, Satu Mustjoki, Panu Kovanen, Martin Eilers, Joel D. Leverson and Juha Klefström ()
Additional contact information
Heidi M. Haikala: University of Helsinki
Johanna M. Anttila: University of Helsinki
Elsa Marques: University of Helsinki
Tiina Raatikainen: University of Helsinki
Mette Ilander: University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center
Henna Hakanen: University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center
Hanna Ala-Hongisto: University of Helsinki
Mariel Savelius: University of Helsinki
Diego Balboa: University of Helsinki
Bjoern Eyss: Fritz Lipmann Institute e.V
Vilja Eskelinen: University of Helsinki
Pauliina Munne: University of Helsinki
Anni I. Nieminen: University of Helsinki
Timo Otonkoski: University of Helsinki
Julia Schüler: Oncotest GmbH, (Now part of Charles River Laboratories Inc, 251 Ballardvale St, Wilmington, MA 01887, USA)
Teemu D. Laajala: University of Helsinki
Tero Aittokallio: University of Helsinki
Harri Sihto: University of Helsinki
Johanna Mattson: University of Helsinki and Helsinki University Hospital
Päivi Heikkilä: University of Helsinki and Helsinki University Hospital
Marjut Leidenius: Helsinki University Hospital
Heikki Joensuu: University of Helsinki
Satu Mustjoki: University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center
Panu Kovanen: University of Helsinki and Helsinki University Hospital
Martin Eilers: Biocenter, University of Würzburg
Joel D. Leverson: AbbVie, Inc.
Juha Klefström: University of Helsinki

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-08541-2

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