@article{008b099a4f7443d283a53f558548419d,
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",
note = "Funding Information: We are grateful to our patients for their time and precious tissue samples. We thank Setareh Sharzehi, Jack Sumner, Massively Parallel Sequencing Shared Resource, and Flow Cytometry core for technical support; and Stephen Christy for organization of patient sample accrual. We thank Stephen E. Kurtz and TingTing Liu for helpful discussions, and Robert L. Raffai (UCSF) for critical review of the manuscript. AZD2811 was kindly provided by AstraZeneca. We thank the U.S. National Cancer Institute's Office of Cancer Clinical Proteomics Research (Clinical Proteomic Tumor Analysis Consortium [CPTAC]) for their support with international organizations/institutions to accelerate the understanding of the molecular basis of cancer through the application of proteogenomics, standards development, and publicly available datasets. This work was supported by the American Cancer Society (MRSG-17-040-01-LIB), Hildegard Lamfrom Physician Scientist Award, and funding from the Leukemia & Lymphoma Society to E.T. the CPTAC (U01CA214116 and U24CA210955), the Drug Sensitivity and Resistance Network (U54CA224019), and the Cancer Target Discovery and Development Network (U01CA217862) from the NCI to B.J.D. K.D.R. T.L. and J.W.T. Additional funding was provided by the HHMI to B.J.D. S.K.J. is supported by the ARCS Scholar Foundation, The Paul & Daisy Soros Fellowship, and the NCI (F30CA239335). T.N. is supported by the NCI (R50CA251708). A.D'A. and J.A.R. acknowledge support from the NCI (P30CA046934). Conceptualization, S.K.J. and E.T.; methodology, S.K.J. T.N. D.B. P.D.P. J.A.R. Y.-T.W. O.B. A.D'A. T.L. S.K.M. and K.D.R.; investigation, S.K.J. T.N. P.D.P. J.A.R. J.P. Y.-T.W. J.R.H. F.C. M.A.G. C.H. K.K.W. T.L.F. J.E.McD. and T.L.; formal analysis, S.K.J. T.N. D.B. P.D.P. J.A.R. A.K. S.J.C.G. Y.-T.W. J.M. F.C. C.-F.T. A.A.S. T.S. O.A.A. J.E.McD. O.B. K.W.-S. E.D. A.D. T.L. C.E.T. J.W.T. S.K.M. K.D.R. B.J.D. and E.T.; data curation, S.K.J. D.B. A.K. S.J.C.G. and S.K.McW.; writing – original draft, S.K.J. and E.T.; writing – review & editing, S.K.J. T.N. D.B. P.D.P. J.A.R. J.P. A.K. S.J.C.G. Y.-T.W. J.R.H. M.A.G. C.H. K.K.W. J.M. T.L.F. C.-F.T. A.A.S. T.S. O.A.A. J.E.McD. O.B. K.W.-S. E.D. A.D'A. T.L. C.E.T. J.W.T. S.K.McW. K.D.R. B.J.D. and E.T.; visualization, S.K.J. D.B. and J.A.R.; supervision, S.K.J. and E.T.; funding acquisition, J.W.T. K.R. B.J.D. and E.T. B.J.D. potential competing interests—SAB: Aileron Therapeutics, Therapy Architects (ALLCRON), Cepheid, Vivid Biosciences, Celgene, RUNX1 Research Program, Novartis, Gilead Sciences (inactive), Monojul (inactive); SAB & Stock: Aptose Biosciences, Blueprint Medicines, EnLiven Therapeutics, Iterion Therapeutics, Third Coast Therapeutics, GRAIL (SAB inactive); Scientific Founder: MolecularMD (inactive, acquired by ICON); Board of Directors & Stock: Amgen, Vincera Pharma; Board of Directors: Burroughs Wellcome Fund, CureOne; Joint Steering Committee: Beat AML LLS; Founder: VB Therapeutics; Sponsored Research Agreement: EnLiven Therapeutics; Clinical Trial Funding: Novartis, Bristol-Myers Squibb, Pfizer; Royalties from Patent 6958335 (Novartis exclusive license) and OHSU and Dana-Farber Cancer Institute (one Merck exclusive license and one CytoImage, Inc. exclusive license). E.T. potential competing interests—Advisory Board/Consulting: Abbvie, Agios, Astellas, Daiichi-Sankyo; Clinical Trial Funding: Janssen, Incyte, LLS BeatAML. Stock options: Notable Labs. J.W.T. potential competing interests—research support: Agios, Aptose, Array, AstraZeneca, Constellation, Genentech, Gilead, Incyte, Janssen, Petra, Seattle Genetics, Syros, Tolero and Takeda. A.D. potential competing interests—founder: Omix Technologies, Inc. and Altis Biosciences, LLC; Consultant: Hemanext Inc. All other authors declare no potential competing interests. Funding Information: We are grateful to our patients for their time and precious tissue samples. We thank Setareh Sharzehi, Jack Sumner, Massively Parallel Sequencing Shared Resource, and Flow Cytometry core for technical support; and Stephen Christy for organization of patient sample accrual. We thank Stephen E. Kurtz and TingTing Liu for helpful discussions, and Robert L. Raffai (UCSF) for critical review of the manuscript. AZD2811 was kindly provided by AstraZeneca. We thank the U.S. National Cancer Institute's Office of Cancer Clinical Proteomics Research (Clinical Proteomic Tumor Analysis Consortium [CPTAC]) for their support with international organizations/institutions to accelerate the understanding of the molecular basis of cancer through the application of proteogenomics, standards development, and publicly available datasets. This work was supported by the American Cancer Society ( MRSG-17-040-01-LIB ), Hildegard Lamfrom Physician Scientist Award, and funding from the Leukemia & Lymphoma Society to E.T., the CPTAC ( U01CA214116 and U24CA210955 ), the Drug Sensitivity and Resistance Network ( U54CA224019 ), and the Cancer Target Discovery and Development Network ( U01CA217862 ) from the NCI to B.J.D., K.D.R., T.L., and J.W.T. Additional funding was provided by the HHMI to B.J.D. S.K.J. is supported by the ARCS Scholar Foundation, The Paul & Daisy Soros Fellowship, and the NCI ( F30CA239335 ). T.N. is supported by the NCI ( R50CA251708 ). A.D{\textquoteright}A. and J.A.R. acknowledge support from the NCI ( P30CA046934 ). Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = jul,
day = "12",
doi = "10.1016/j.ccell.2021.06.003",
language = "English (US)",
volume = "39",
pages = "999--1014.e8",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "7",
}