The AML microenvironment catalyzes a stepwise evolution to gilteritinib resistance

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. ArshadJason 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

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)999-1014.e8
JournalCancer Cell
Volume39
Issue number7
DOIs
StatePublished - Jul 12 2021

Keywords

  • AML
  • Aurora kinase B
  • FLT3
  • NRAS
  • drug resistance
  • gilteritinib
  • lipid metabolism
  • quizartinib
  • tumor microenvironment
  • tyrosine kinase inhibitor

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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