Abstract LB-189: Pharmacological reactivation of MYC-dependent apoptosis cooperates with anti-PD1 immunotherapy

Elevated MYC levels sensitize 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 dramatically synergizes with BCL-2/BCL-XL inhibitors to activate MYC-dependent 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 either navitoclax or venetoclax efficiently inhibits tumor growth, confers survival benefits and induces tumor infiltration by immune cells. However, withdrawal of the drugs allowed tumor re- growth with presentation of PD1+/CD8+ T cell infiltrates, suggesting immune escape. A two-step treatment regimen, beginning with neoadjuvant metformin+venetoclax to induce apoptosis and followed by tumor resection and adjuvant metformin+venetoclax+anti-PD1 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. Citation Format: Heidi M. Haikala, Johanna M. Anttila, Mariel Savelius, Elsa Marques, Tiina Raatikainen, Mette Ilander, Henna Hakanen, Johanna Mattson, Paivi Heikkila, Marjut Leidenius, Heikki Joensuu, Satu Mustjoki, Panu Kovanen, Martin Eilers, Joel D. Leverson, Juha T. Klefstrom. Pharmacological reactivation of MYC-dependent apoptosis cooperates with anti-PD1 immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-189.