The PIP4K2 inhibitor THZ-P1-2 exhibits antileukemia activity by disruption of mitochondrial homeostasis and autophagy

• DOI: 10.1038/s41408-022-00747-w
• Publication Date: 2022-11-09T01:02:44Z
• Authors: Keli Lima; Diego Antonio Per...; Lívia Bassani Lin...; Juan Luiz Coelho-...; Giovana da Silva ...; Isabel Weinhäuser; Rita de Cássia Ca...; Aline de Medeiros...; Wellington Fernan...; Ana Paula Alencar...; Elvira Deolinda R...; Emmanuel Griessinger; Jacobien R. Hilbe...; Emanuele Ammatuna; Gerwin Huls; Jan Jacob Schuringa; Eduardo Magalhães...; João Agostinho Ma...
• Keywords: 0301 basic medicine; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Apoptosis; Article; 3. Good health; Leukemia, Myeloid, Acute; 03 medical and health sciences; Tandem Mass Spectrometry; Autophagy; Humans; Homeostasis; RC254-282; Chromatography, Liquid

AbstractThe treatment of acute leukemia is challenging because of the genetic heterogeneity between and within patients. Leukemic stem cells (LSCs) are relatively drug-resistant and frequently relapse. Their plasticity and capacity to adapt to extracellular stress, in which mitochondrial metabolism and autophagy play important roles, further complicates treatment. Genetic models of phosphatidylinositol-5-phosphate 4-kinase type 2 protein (PIP4K2s) inhibition have demonstrated the relevance of these enzymes in mitochondrial homeostasis and autophagic flux. Here, we uncovered the cellular and molecular effects of THZ-P1-2, a pan-inhibitor of PIP4K2s, in acute leukemia cells. THZ-P1-2 reduced cell viability and induced DNA damage, apoptosis, loss of mitochondrial membrane potential, and the accumulation of acidic vesicular organelles. Protein expression analysis revealed that THZ-P1-2 impaired autophagic flux. In addition, THZ-P1-2 induced cell differentiation and showed synergistic effects with venetoclax. In primary leukemia cells, LC-MS/MS-based proteome analysis revealed that sensitivity to THZ-P1-2 is associated with mitochondrial metabolism, cell cycle, cell-of-origin (hematopoietic stem cell and myeloid progenitor), and the TP53 pathway. The minimal effects of THZ-P1-2 observed in healthy CD34+cells suggest a favorable therapeutic window. Our study provides insights into the pharmacological inhibition of PIP4K2s targeting mitochondrial homeostasis and autophagy, shedding light on a new class of drugs for acute leukemia.