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. 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

doi:10.1016/j.ccell.2021.06.003

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

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53 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 language	English (US)
Pages (from-to)	999-1014.e8
Journal	Cancer Cell
Volume	39
Issue number	7
DOIs	https://doi.org/10.1016/j.ccell.2021.06.003
State	Published - 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
Cancer Research

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10.1016/j.ccell.2021.06.003

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Joshi, S. K., Nechiporuk, T., Bottomly, D., Piehowski, P. D., Reisz, J. A., Pittsenbarger, J., Kaempf, A., Gosline, S. J. C., Wang, Y. T., Hansen, J. R., Gritsenko, M. A., Hutchinson, C., Weitz, K. K., Moon, J., Cendali, F., Fillmore, T. L., Tsai, C. F., Schepmoes, A. A., Shi, T., ... Traer, E. (2021). The AML microenvironment catalyzes a stepwise evolution to gilteritinib resistance. Cancer Cell, 39(7), 999-1014.e8. https://doi.org/10.1016/j.ccell.2021.06.003

Joshi, SK, Nechiporuk, T, Bottomly, D, Piehowski, PD, Reisz, JA, Pittsenbarger, J, Kaempf, A, Gosline, SJC, Wang, YT, Hansen, JR, Gritsenko, MA, Hutchinson, C, Weitz, KK, Moon, J, Cendali, F, Fillmore, TL, Tsai, CF, Schepmoes, AA, Shi, T, Arshad, OA, McDermott, JE, Babur, O, Watanabe-Smith, K , Demir, E, D'Alessandro, A, Liu, T, Tognon, CE , Tyner, JW , McWeeney, SK, Rodland, KD, Druker, BJ & Traer, E 2021, 'The AML microenvironment catalyzes a stepwise evolution to gilteritinib resistance', Cancer Cell, vol. 39, no. 7, pp. 999-1014.e8. https://doi.org/10.1016/j.ccell.2021.06.003

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title = "The AML microenvironment catalyzes a stepwise evolution to gilteritinib resistance",

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.",

keywords = "AML, Aurora kinase B, FLT3, NRAS, drug resistance, gilteritinib, lipid metabolism, quizartinib, tumor microenvironment, tyrosine kinase inhibitor",

author = "Joshi, {Sunil K.} and Tamilla Nechiporuk and Daniel Bottomly and Piehowski, {Paul D.} and Reisz, {Julie A.} and Jan{\'e}t Pittsenbarger and Andy Kaempf and Gosline, {Sara J.C.} and Wang, {Yi Ting} and Hansen, {Joshua R.} and Gritsenko, {Marina A.} and Chelsea Hutchinson and Weitz, {Karl K.} and Jamie Moon and Francesca Cendali and Fillmore, {Thomas L.} and Tsai, {Chia Feng} and Schepmoes, {Athena A.} and Tujin Shi and Arshad, {Osama A.} and McDermott, {Jason E.} and Ozgun Babur and Kevin Watanabe-Smith and Emek Demir and Angelo D'Alessandro and Tao Liu and Tognon, {Cristina E.} and Tyner, {Jeffrey W.} and McWeeney, {Shannon K.} and Rodland, {Karin D.} and Druker, {Brian J.} and Elie Traer",

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T1 - The AML microenvironment catalyzes a stepwise evolution to gilteritinib resistance

AU - Joshi, Sunil K.

AU - Nechiporuk, Tamilla

AU - Bottomly, Daniel

AU - Piehowski, Paul D.

AU - Reisz, Julie A.

AU - Pittsenbarger, Janét

AU - Kaempf, Andy

AU - Gosline, Sara J.C.

AU - Wang, Yi Ting

AU - Hansen, Joshua R.

AU - Gritsenko, Marina A.

AU - Hutchinson, Chelsea

AU - Weitz, Karl K.

AU - Moon, Jamie

AU - Cendali, Francesca

AU - Fillmore, Thomas L.

AU - Tsai, Chia Feng

AU - Schepmoes, Athena A.

AU - Shi, Tujin

AU - Arshad, Osama A.

AU - McDermott, Jason E.

AU - Babur, Ozgun

AU - Watanabe-Smith, Kevin

AU - Demir, Emek

AU - D'Alessandro, Angelo

AU - Liu, Tao

AU - Tognon, Cristina E.

AU - Tyner, Jeffrey W.

AU - McWeeney, Shannon K.

AU - Rodland, Karin D.

AU - Druker, Brian J.

AU - Traer, Elie

PY - 2021/7/12

Y1 - 2021/7/12

N2 - 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.

AB - 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.

KW - AML

KW - Aurora kinase B

KW - FLT3

KW - NRAS

KW - drug resistance

KW - gilteritinib

KW - lipid metabolism

KW - quizartinib

KW - tumor microenvironment

KW - tyrosine kinase inhibitor

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DO - 10.1016/j.ccell.2021.06.003

M3 - Article

C2 - 34171263

AN - SCOPUS:85111786579

SN - 1535-6108

VL - 39

SP - 999-1014.e8

JO - Cancer Cell

JF - Cancer Cell

IS - 7

ER -

The AML microenvironment catalyzes a stepwise evolution to gilteritinib resistance

Abstract

Keywords

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