PLK1 Inhibition Induces Synthetic Lethality in Fanconi Anemia Pathway–Deficient Acute Myeloid Leukemia

• DOI: 10.1158/2767-9764.crc-24-0260
• Publication Date: 2025-03-20T13:39:18Z
• Authors: Aditya S. Sheth; Ka-Kui Chan; Sheng Liu; Jun Wan; Steve P. Angus; Steven D. Rhodes; Dana K. Mitchell; Christopher Davis; Maya Ridinger; Peter J. Croucher; Amer M. Zeidan; Aruna Wijeratne; Shaomin Qian; Ngoc Tung Tran; Elizabeth A. Sier...
• Keywords: PLK1; FANCA; FANCD2; Synthetic Lethality

Abstract Overall survival of acute myeloid leukemia (AML) remains limited. Inhibitors the master mitotic kinase PLK1 have emerged as promising therapeutics, demonstrating efficacy in an undefined subset AML patients. However, clinical success inhibitors hindered by a lack predictive biomarkers. The Fanconi anemia (FA) pathway, tumor-suppressive network comprised at least 22 genes, is frequently mutated sporadic AML. Here, we demonstrate that FA pathway disruption sensitizes cells to inhibition. Mechanistically, identify novel interactions between and both FANCA FANCD2 centromeres. We inhibition impairs recruitment centromeres, induces damage chromosomes, triggers collapse FANCA-deficient cells. Our findings indicate targets vulnerabilities specific pathway-deficient implicate mutations potential biomarkers for identification patients likely benefit from inhibitors.