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

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-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds / pharmacology
  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis / immunology
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / pathology
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • CD8-Positive T-Lymphocytes
  • Cell Line, Tumor / drug effects
  • Cell Survival / drug effects
  • Clustered Regularly Interspaced Short Palindromic Repeats
  • Drug Combinations
  • Female
  • Genes, myc / drug effects*
  • HEK293 Cells
  • Heterografts
  • Humans
  • Immunotherapy*
  • Metformin / pharmacology
  • Mice
  • Mice, Transgenic
  • Proto-Oncogene Proteins c-bcl-2
  • Sulfonamides / pharmacology
  • bcl-X Protein


  • Aniline Compounds
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • BCL2 protein, human
  • Bcl2l1 protein, mouse
  • Bridged Bicyclo Compounds, Heterocyclic
  • Drug Combinations
  • Proto-Oncogene Proteins c-bcl-2
  • Sulfonamides
  • bcl-X Protein
  • atezolizumab
  • Metformin
  • venetoclax
  • navitoclax