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Pitavastatin counteracts venetoclax resistance mechanisms in acute myeloid leukemia by depleting geranylgeranyl

Roberta Buono1, Dennis Juarez1, Madhuri Paul1

  • 1Department of Molecular Biology & Biochemistry, University of California Irvine, Irvine, CA, 92697, USA.

Biorxiv : the Preprint Server for Biology
|November 24, 2025
PubMed

Insights

Pitavastatin overcomes venetoclax resistance in acute myeloid leukemia (AML) by upregulating PUMA and reducing MCL-1. This HMG-CoA-reductase inhibitor shows promise for treating AML patients resistant to venetoclax-based therapies.

Area of Science:

  • Hematology
  • Oncology
  • Molecular Biology

Background:

  • Venetoclax is a BCL2 inhibitor effective in hematological malignancies like AML.
  • Resistance to venetoclax, particularly in TP53-mutant AML, is a significant clinical challenge.
  • Mechanisms of resistance include TP53 mutations, FLT3 mutations, MCL-1 upregulation, and altered mitochondrial metabolism.

Purpose of the Study:

  • To investigate pitavastatin's potential to overcome venetoclax resistance in AML.
  • To elucidate the molecular mechanisms by which pitavastatin exerts its anti-leukemic effects.

Main Methods:

  • Utilized human AML cell lines with common resistance mutations (TP53, FLT3).
  • Assessed pitavastatin's cytotoxic activity and apoptotic effects.
  • Investigated changes in apoptosis-related proteins (PUMA, MCL-1) and mitochondrial metabolism.
  • Examined the role of geranylgeranyl pyrophosphate (GGPP) depletion.

Main Results:

  • Pitavastatin demonstrated potent cytotoxic activity in AML cells with TP53 or FLT3 mutations.
  • Pitavastatin induced apoptosis via p53-independent PUMA upregulation and MCL-1 downregulation.
  • The drug suppressed mitochondrial gene expression and oxidative metabolism.
  • Pitavastatin's pro-apoptotic effects were linked to GGPP depletion.

Conclusions:

  • Pitavastatin effectively overcomes multiple venetoclax resistance mechanisms in AML.
  • Pitavastatin exhibits anti-leukemic activity through modulation of apoptotic pathways and mitochondrial function.
  • These findings support the potential of pitavastatin as an adjunct therapy to enhance venetoclax efficacy in AML.

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