1. Academic Validation
  2. Targeting MCL-1 triggers DNA damage and an anti-proliferative response independent from apoptosis induction

Targeting MCL-1 triggers DNA damage and an anti-proliferative response independent from apoptosis induction

  • Cell Rep. 2023 Sep 27;42(10):113176. doi: 10.1016/j.celrep.2023.113176.
Utsarga Adhikary 1 Joao A Paulo 2 Marina Godes 1 Shrabasti Roychoudhury 3 Michelle S Prew 1 Yael Ben-Nun 1 Ellen W Yu 1 Amit Budhraja 4 Joseph T Opferman 4 Dipanjan Chowdhury 3 Steven P Gygi 2 Loren D Walensky 5
Affiliations

Affiliations

  • 1 Department of Pediatric Oncology and Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 2 Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
  • 3 Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 4 Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 5 Department of Pediatric Oncology and Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: loren_walensky@dfci.harvard.edu.
Abstract

Mcl-1 is a high-priority target due to its dominant role in the pathogenesis and chemoresistance of Cancer, yet clinical trials of Mcl-1 inhibitors are revealing toxic side effects. Mcl-1 biology is complex, extending beyond apoptotic regulation and confounded by its multiple isoforms, its domains of unresolved structure and function, and challenges in distinguishing noncanonical activities from the apoptotic response. We find that, in the presence or absence of an intact mitochondrial apoptotic pathway, genetic deletion or pharmacologic targeting of Mcl-1 induces DNA damage and retards cell proliferation. Indeed, the Cancer cell susceptibility profile of Mcl-1 inhibitors better matches that of anti-proliferative than pro-apoptotic drugs, expanding their potential therapeutic applications, including synergistic combinations, but heightening therapeutic window concerns. Proteomic profiling provides a resource for mechanistic dissection and reveals the minichromosome maintenance DNA helicase as an interacting nuclear protein complex that links Mcl-1 to the regulation of DNA integrity and cell-cycle progression.

Keywords

BCL-2 family; CP: Cancer; CP: Molecular biology; DNA damage; MCL-1; apoptosis; cancer; cell cycle; cell proliferation; chemotherapy; minichrosome maintenance complex; proteomics.

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