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

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.

BCL-2 antagonism sensitizes cytotoxic T cell–resistant HIV reservoirs to elimination ex vivo

“…73). Moreover, in a murine cancer model, venetoclax enhanced anti-PD-1-mediated T cell antitumor activity (73,74). In conclusion, the current study provides evidence that HIV reservoir-harboring cells have been selected for survivability, conferred, at least in part, through BCL-2.…”

Metformin as an archetype immuno-metabolic adjuvant for cancer immunotherapy

“…84 Such translational potential of metformin to convert immunotherapy-resistant patients into those showing clinical benefit has been supported by the discovery that adjuvant metformin plus anti-PD-1 treatment results in durable antitumor responses by preventing the presentation of PD-1 + / CD8 + T-cell infiltrates after drug withdrawal. 85 A retrospective cohort study including patients diagnosed with metastatic malignant melanoma and treated with anti-PD-1 only or anti-CTLA4/ anti-PD-1 combination therapies, with or without metformin, revealed favorable treatment-related outcomes in terms of objective response rate, disease control rate, overall survival, and progression-free survival in patients who have received metformin in combination with immune-checkpoint inhibitors, albeit without reaching statistical significance likely due to the small sample size. 86 An analysis of the immunomodulatory effects of metformin in a clinical trial of head and neck squamous cell carcinoma revealed its ability to increase both CD8 + effector T-cells and FoxP3 + T reg cell infiltrates in the TME.…”

Chemical, physical and biological triggers of evolutionary conserved Bcl-xL-mediated apoptosis

“…To obtain additive or synergistic effects, enhance efficacy of treatment and combat genetically heterogeneous cancers, Bcl-2 inhibitors were combined with other anticancer drugs ( Fig. S1c; bcl2icombi.info) (Chen, Jin et al, 2011, Haikala, Anttila et al, 2019, Jeong, Oh et al, 2019, Shen, Li et al, 2018. The drug combinations were also used to lower the dose of Bcl-2 inhibitors to overcome resistance and toxicity issues for non-malignant cells (Adams et al, 2018).…”