The AML microenvironment catalyzes a stepwise evolution to gilteritinib resistance

• DOI: 10.1016/j.ccell.2021.06.003
• Publication Date: 2021-06-24T14:46:30Z
• Authors: Sunil K. Joshi; Tamilla Nechiporuk; Daniel Bottomly; Paul D. Piehowski; Julie A. Reisz; Janét Pittsenbarger; Andy Kaempf; Sara J.C. Gosline; Yi-Ting Wang; Joshua R. Hansen; Marina A. Gritsenko; Chelsea Hutchinson; Karl K. Weitz; Jamie Moon; Francesca Cendali; Thomas L. Fillmore; Chia-Feng Tsai; Athena A. Schepmoes; Tujin Shi; Osama A. Arshad; Jason E. McDermott; Ozgun Babur; Kevin Watanabe-Smith; Emek Demir; Angelo D'Alessandro; Tao Liu; Cristina E. Tognon; Jeffrey W. Tyner; Shannon K. McWeeney; Karin D. Rodland; Brian J. Druker; Elie Traer
• Keywords: Reprogramming

Our study details the stepwise evolution of gilteritinib resistance in FLT3-mutated acute myeloid leukemia (AML). Early is mediated by bone marrow microenvironment, which protects residual cells. Over time, cells evolve intrinsic mechanisms resistance, or late resistance. We mechanistically define both early and integrating whole-exome sequencing, CRISPR-Cas9, metabolomics, proteomics, pharmacologic approaches. resistant undergo metabolic reprogramming, grow more slowly, are dependent upon Aurora kinase B (AURKB). Late characterized expansion pre-existing NRAS mutant subclones continued reprogramming. model closely mirrors timing mutations AML patients treated with gilteritinib. Pharmacological inhibition AURKB resensitizes cell cultures primary from gilteritinib-treated patients. These findings support a combinatorial strategy to target inhibitors before occurs.