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

Heidi M Haikala,Päivi Heikkilä,Juha Klefström,Julia Schüler,Vilja Eskelinen,Satu Mustjoki,Joel D Leverson,Teemu D Laajala,Heikki Joensuu,Diego Balboa,Tiina Raatikainen,Panu E Kovanen ,Mette Ilander,Mariel Savelius,Marjut Leidenius,Timo Otonkoski,Hanna Ala-Hongisto,Pauliina Munne,Elsa Marques,Anni I Nieminen,Johanna Mattson,Harri Sihto,Martin Eilers,Johanna M Anttila,Henna Hakanen,Tero Aittokallio,Björn Von Eyß

doi:10.1038/s41467-019-08541-2

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.

Highlights

Harvard Medical School, 360 Longwood Ave, 02215 Boston, MA, USA
MYC is a multifunctional oncogenic transcription factor that is frequently overexpressed in cancer
To determine whether primary breast cancer could be targeted by a therapeutic strategy that reactivates MYC’s apoptotic potential via BH3 mimetics, we assessed the expression of MYC, BCL-2, BCL-XL, and MCL-1 using a tissue microarray (TMA) of 231 primary breast cancer samples

Summary

Introduction

Harvard Medical School, 360 Longwood Ave, 02215 Boston, MA, USA. MYC is a multifunctional oncogenic transcription factor that is frequently overexpressed in cancer. MYC protein expression is elevated via altered posttranslational mechanisms and, altogether, about half of breast cancers display elevated MYC protein expression[5]. MYC can promote transcription, via its canonical binding sites, and by occupying low affinity promoters. Such “promoter invasion” may endow cells with new tumor-specific phenotypes[7], including insensitivity to proliferation-restricting signals, altered cell metabolism in support of continuous growth, and effects on the tumor microenvironment[8]. The effects of oncogenic MYC on cell metabolism, host-microenvironment communication, and immunoregulation have all been considered as potential nodes for targeting MYC indirectly[9,10,11,12]

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Results

Conclusion