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CDK4/6 Inhibitor, Palbociclib, overcomes Venetoclax resistance mechanisms and outperforms single agents in Acute Myeloid Leukemia [CRISPR Screen]

ABSTRACT: Venetoclax (ven) combined with the hypomethylating agent azacytidine (aza) is a widely used therapy for Acute Myeloid Leukemia (AML), however, most patients develop resistance. A genome-wide CRISPR screen showed that loss of genes involved in translation conferred sensitivity to ven but not ven+palbo. Accordingly, we show that increased translation occurs after AML cells are challenged with ven, and ven+palbo blocks this increase. We also found that loss of BAX, which leads to ven resistance, was overcome by combination with CDK4/6 inhibitors. Conversely, loss of RB1, a known mechanism of resistance to CDK4/6 inhibitors, was mitigated by ven+palbo. This work suggests that the combination of ven+palbo is a potential novel therapy for AML for potential subpopulations that may benefit the most from this treatment, as well as targeting translation as a means to overcome ven resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE291338 | GEO | 2025/11/11

REPOSITORIES: GEO

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CDK4/6 Inhibitor, Palbociclib, overcomes Venetoclax resistance mechanisms and outperforms single agents in Acute Myeloid Leukemia [RNA-Seq]

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Fatty acid metabolism mediates venetoclax resistance in acute myeloid leukemia stem cells

Project description:The combination of venetoclax with azacitidine (ven/aza) has recently emerged as a promising regimen for acute myeloid leukemia (AML), with approximately 70% of newly diagnosed patients achieving complete remission (CR). However, 30% of newly diagnosed and nearly all relapsed patients do not achieve CR with ven/aza. Mechanistically, we previously reported that ven/aza efficacy is based on eradication of AML stem cells through a mechanism involving inhibition of amino acid metabolism, a process which is required in primitive AML cells to drive oxidative phosphorylation. In the present study we demonstrate that resistance to ven/aza occurs as a consequence of up-regulated fatty acid oxidation (FAO), which occurs either as an intrinsic property of RAS pathway mutations, or as a compensatory adaptation in relapsed disease. Utilization of FAO obviates the need for amino acid metabolism into the TCA cycle, thereby rendering ven/aza ineffective. Importantly, we show that pharmacological inhibition of FAO via use of MCL-1 or CPT1 inhibitor drugs restores targeting of ven/aza resistant AML stem cells. Based on these findings we propose that inhibition of FAO is a potential therapeutic strategy to address ven/aza resistance.

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Targeting the metabolic vulnerability of acute myeloid leukemia blasts with a combination of venetoclax and 8-chloro-adenosine

Project description:Purpose: To show that 8-Cl-Ado can target FAO and synergizes with VEN to significantly decrease the oxygen consumption rate (OCR) and in turn OXPHOS in CD34-enriched AML cells. Methods: Using AML cell lines and LSC-enriched blast cells from pre-treatment AML patients, we evaluated the effects of 8-Cl-Ado, VEN and the 8-Cl-Ado/VEN combination on fatty acid metabolism, glycolysis and OXPHOS using liquid scintillation counting, a Seahorse XF Analyzer and gene set enrichment analysis (GSEA). Results: We here report that VEN and 8-Cl-Ado synergistically inhibited in vitro growth of AML cells. Furthermore, immunodeficient mice engrafted with MV4-11-Luc AML cells and treated with the combination of VEN plus 8-Cl-Ado had a significantly longer survival than mice treated with either drugs alone (p≤0.006). Conclusion: Taken together, the results suggest that 8-Cl-Ado enhances the antileukemic activity of VEN and that this combination represents a promising therapeutic regimen for treatment of AML.

2021-04-07 | GSE171552 | GEO

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