The AML Microenvironment Catalyzes a Stepwise Evolution to Gilteritinib Resistance

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2021 Jun 25

PMID 34171263

Citations 59

Authors

Sunil K Joshi

Tamilla Nechiporuk

Daniel Bottomly

Paul D Piehowski

Julie A Reisz

Janet 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 DAlessandro

Tao Liu

Cristina E Tognon

Jeffrey W Tyner

Shannon K McWeeney

Karin D Rodland

Brian J Druker

Elie Traer

Affiliations

Soon will be listed here.

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.

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