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Statin-induced Mitochondrial Priming Sensitizes Multiple Myeloma Cells to BCL2 and MCL-1 Inhibitors

Dennis Juarez1, Roberta Buono1, Shannon M Matulis2

  • 1Department of Molecular Biology and Biochemistry, University of California, Irvine, California.

Cancer Research Communications
|November 13, 2023
PubMed

Insights

Statins can overcome resistance to venetoclax in multiple myeloma by upregulating proapoptotic proteins. Clinical data suggest statins enhance venetoclax response, supporting their combination in blood cancer treatment.

Area of Science:

  • Hematology
  • Oncology
  • Molecular Biology

Background:

  • Venetoclax, a BCL2 inhibitor, is effective in certain blood cancers but faces resistance in multiple myeloma due to MCL-1 dependency.
  • Multiple myeloma cells often rely on MCL-1 for survival, limiting the efficacy of venetoclax.
  • There is a need for rational combinations to improve the efficacy of BH3 mimetics like venetoclax in multiple myeloma.

Purpose of the Study:

  • To investigate whether statins can overcome venetoclax resistance in multiple myeloma.
  • To explore the mechanisms by which statins sensitize multiple myeloma cells to apoptosis.
  • To evaluate the clinical association of statin use with venetoclax treatment outcomes in multiple myeloma.

Main Methods:

  • Inhibition of the mevalonate pathway using statins in multiple myeloma cell lines and primary cells.
  • Assessment of apoptosis induction by statins in combination with venetoclax and MCL-1 inhibitor S63845.
  • Retrospective analysis of clinical data from venetoclax studies in multiple myeloma patients, examining background statin use.
  • Investigation of proapoptotic protein upregulation (PUMA, NOXA) mediated by statins.

Main Results:

  • Statins overcame venetoclax resistance in multiple myeloma cell lines and primary cells.
  • Statins sensitized cells to apoptosis induced by both venetoclax and the MCL-1 inhibitor S63845.
  • Retrospective analysis showed background statin use was associated with improved stringent complete response rates and reduced disease progression in venetoclax-treated multiple myeloma patients.
  • Statins upregulated proapoptotic proteins PUMA (p53-independent) and NOXA (via integrated stress response), sensitizing cells to venetoclax.

Conclusions:

  • Mevalonate pathway inhibition with statins is a viable strategy to overcome venetoclax resistance in multiple myeloma.
  • Statins enhance apoptosis by upregulating PUMA and NOXA, providing a mechanistic basis for their efficacy.
  • Clinical data suggest a beneficial association between statin use and venetoclax treatment outcomes in multiple myeloma.
  • These findings support the prospective evaluation of statins in combination with venetoclax regimens for multiple myeloma treatment.

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