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Pharmacological reactivation of MYC-dependent apoptosis induces susceptibility to anti-PD-1 immunotherapy.
- Source :
-
Nature communications [Nat Commun] 2019 Feb 06; Vol. 10 (1), pp. 620. Date of Electronic Publication: 2019 Feb 06. - Publication Year :
- 2019
-
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-X <subscript>L</subscript> inhibitors to activate apoptosis. We demonstrate the translational potential of an AMPK and BCL-2/BCL-X <subscript>L</subscript> 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.
- Subjects :
- Aniline Compounds pharmacology
Animals
Antibodies, Monoclonal, Humanized
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
HEK293 Cells
Heterografts
Humans
Metformin pharmacology
Mice
Mice, Transgenic
Proto-Oncogene Proteins c-bcl-2
Sulfonamides pharmacology
bcl-X Protein
Antibodies, Monoclonal pharmacology
Antineoplastic Agents pharmacology
Apoptosis drug effects
Genes, myc drug effects
Immunotherapy
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 10
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 30728358
- Full Text :
- https://doi.org/10.1038/s41467-019-08541-2