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.
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 360 Longwood Ave, 02215, Boston, MA, USA.
Nat Commun. 2019 Feb 6;10(1):620. doi: 10.1038/s41467-019-08541-2.
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-X inhibitors to activate apoptosis. We demonstrate the translational potential of an AMPK and BCL-2/BCL-X 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.
MYC 表达升高使肿瘤细胞对细胞凋亡敏感，但这种机制的治疗潜力尚不清楚。我们在 MYC 驱动的乳腺癌模型中发现，AMPK 的药理学激活与 BCL-2/BCL-X 抑制剂强烈协同作用，激活细胞凋亡。我们在 MYC 高表达乳腺癌的离体和体内模型中证明了 AMPK 和 BCL-2/BCL-X 共同靶向策略的转化潜力。二甲双胍联合 navitoclax 或 venetoclax 可有效抑制肿瘤生长，带来生存获益，并诱导免疫细胞浸润肿瘤。然而，停药后肿瘤重新生长，出现 PD-1+/CD8+T 细胞浸润，提示免疫逃逸。两步治疗方案，先用新辅助治疗的二甲双胍+venetoclax 诱导细胞凋亡，然后用辅助治疗的二甲双胍+venetoclax+抗 PD-1 治疗来克服免疫逃逸，即使停药后也能产生持久的抗肿瘤反应。我们证明，依赖 MYC 的细胞凋亡的药理学再激活是一种强大的抗肿瘤策略，涉及肿瘤细胞耗竭和免疫监视。
