A1 Refereed original research article in a scientific journal
Pharmacological reactivation of MYC-dependent apoptosis induces susceptibility to anti-PD-1 immunotherapy
Authors: Haikala HM, Anttila JM, Marques E, Raatikainen T, Ilander M, Hakanen H, Ala-Hongisto H, Savelius M, Balboa D, Von Eyss B, Eskelinen V, Munne P, Nieminen AI, Otonkoski T, Schuler J, Laajala TD, Aittokallio T, Sihto H, Mattson J, Heikkila P, Leidenius M, Joensuu H, Mustjoki S, Kovanen P, Eilers M, Leverson JD, Klefstrom J, Klefstrom J
Publisher: NATURE PUBLISHING GROUP
Publication year: 2019
Journal: Nature Communications
Journal name in source: NATURE COMMUNICATIONS
Journal acronym: NAT COMMUN
Article number: ARTN 620
Volume: 10
Number of pages: 17
ISSN: 2041-1723
eISSN: 2041-1723
DOI: https://doi.org/10.1038/s41467-019-08541-2
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/39670264
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-L inhibitors to activate apoptosis. We demonstrate the translational potential of an AMPK and BCL-2/BCL-X-L 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.
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