The AML microenvironment catalyzes a step-wise evolution to gilteritinib resistance

Joshi, Sunil K.; Nechiporuk, Tamilla; Bottomly, Daniel; Piehowski, Paul D.; Reisz, Julie; Pittsenbarger, Janet; Kaempf, Andy; Gosline, Sara JC; Wang, Yi-Ting; Hansen, Joshua R.; Gritsenko, Marina A.; Hutchinson, Chelsea M.; Weitz, Karl K.; Moon, Jamie; Cendali, Francesca; Fillmore, Thomas L.; Tsai, Chia-Feng; Schepmoes, Athena A.; Shi, Tujin; Arshad, Osama A.; McDermott, Jason E.; Babur, Ozgun; Watanabe-Smith, Kevin; Demir, Emek; D'Alessandro, Angelo; Liu, Tao; Tognon, Cristina E.; Tyner, Jeffrey W.; Mcweeney, Shannon K.; Rodland, Karin D.; Druker, Brian; Traer, Elie

doi:10.1016/j.ccell.2021.06.003

The AML microenvironment catalyzes a step-wise evolution to gilteritinib resistance

Journal Article · 12 July 2021 · Cancer Cell

DOI:https://doi.org/10.1016/j.ccell.2021.06.003· OSTI ID:1821197

Joshi, Sunil K. ^[1]; Nechiporuk, Tamilla ^[1]; Bottomly, Daniel ^[1]; ^[2]; Reisz, Julie ^[3]; Pittsenbarger, Janet ^[1]; Kaempf, Andy ^[1]; Gosline, Sara JC ^[2]; Wang, Yi-Ting ^[2]; ^[2]; ^[2]; Hutchinson, Chelsea M. ^[2]; Weitz, Karl K. ^[2]; Moon, Jamie ^[2]; Cendali, Francesca ^[4]; Fillmore, Thomas L. ^[2]; Tsai, Chia-Feng ^[2]; Schepmoes, Athena A. ^[2]; Shi, Tujin ^[2]; Arshad, Osama A. ^[2] more »

Oregon Health & Science University
BATTELLE (PACIFIC NW LAB)
University of Colorado
University of Colorado Anschutz Medical Campus
Oregon State University
OREGON HEALTH SCIENCES UNIVERSITY

This study reports a stepwise evolution of gilteritinib resistance in acute myeloid leukemia (AML) relapse, and identifies therapeutic vulnerabilities that could be exploited. Our in vitro model demonstrates that extrinsic microenvironmental factors within the bone marrow nurture the growth of residual cells that underlie early gilteritinib resistance. These early resistant cells exhibit a dependency upon Aurora B (AURKB) and undergo dynamic metabolic adaptations that fostered their transition to late resistance. In line with clinical observations of gilteritinib resistance, late resistant cells displayed an expansion of NRAS mutant subclones and a unique metabolic profile that originated during early resistance. Pharmacological inhibition of AURKB resensitized early resistant cells to gilteritinib. Early resistant cells from AML patients were found to display exquisite sensitivitye to AURKB inhibition. Together, our findings support that eradication of early resistant AML cells may increase the efficacy and durability of gilteritinib.

Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

Sponsoring Organization:: USDOE

DOE Contract Number:: AC05-76RL01830

OSTI ID:: 1821197

Report Number(s):: PNNL-SA-161620

Journal Information:: Cancer Cell, Vol. 39, Issue 7

Country of Publication:: United States

Language:: English

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He, Licai; Shi, Liuzhi; Du, Zhuanyun; +7 more

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