Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms

Haijiao Zhang, Samantha Savage, Anna Reister Schultz, Daniel Bottomly, Libbey White, Erik Segerdell, Beth Wilmot, Shannon K. McWeeney, Christopher A. Eide, Tamilla Nechiporuk, Amy Carlos, Rachel Henson, Chenwei Lin, Robert Searles, Hoang Ho, Yee Ling Lam, Richard Sweat, Courtney Follit, Vinay Jain, Evan Lind, Gautam Borthakur, Guillermo Garcia-Manero, Farhad Ravandi, Hagop M. Kantarjian, Jorge Cortes, Robert Collins, Daelynn R. Buelow, Sharyn D. Baker, Brian J. Druker and Jeffrey W. Tyner ()
Additional contact information
Haijiao Zhang: Oregon Health & Science University Knight Cancer Institute
Samantha Savage: Oregon Health & Science University Knight Cancer Institute
Anna Reister Schultz: Oregon Health & Science University Knight Cancer Institute
Daniel Bottomly: Oregon Health & Science University Knight Cancer Institute
Libbey White: Oregon Health & Science University Knight Cancer Institute
Erik Segerdell: Oregon Health & Science University Knight Cancer Institute
Beth Wilmot: Oregon Health & Science University Knight Cancer Institute
Shannon K. McWeeney: Oregon Health & Science University Knight Cancer Institute
Christopher A. Eide: Oregon Health & Science University Knight Cancer Institute
Tamilla Nechiporuk: Oregon Health & Science University Knight Cancer Institute
Amy Carlos: Oregon Health & Science University Knight Cancer Institute
Rachel Henson: Oregon Health & Science University Knight Cancer Institute
Chenwei Lin: Oregon Health & Science University Knight Cancer Institute
Robert Searles: Oregon Health & Science University Knight Cancer Institute
Hoang Ho: AROG Pharmaceuticals
Yee Ling Lam: AROG Pharmaceuticals
Richard Sweat: AROG Pharmaceuticals
Courtney Follit: AROG Pharmaceuticals
Vinay Jain: AROG Pharmaceuticals
Evan Lind: Oregon Health & Science University Knight Cancer Institute
Gautam Borthakur: The University of Texas MD Anderson Cancer Center
Guillermo Garcia-Manero: The University of Texas MD Anderson Cancer Center
Farhad Ravandi: The University of Texas MD Anderson Cancer Center
Hagop M. Kantarjian: The University of Texas MD Anderson Cancer Center
Jorge Cortes: The University of Texas MD Anderson Cancer Center
Robert Collins: University of Texas Southwestern Medical Center
Daelynn R. Buelow: The Ohio State University College of Pharmacy and Comprehensive Cancer Center
Sharyn D. Baker: The Ohio State University College of Pharmacy and Comprehensive Cancer Center
Brian J. Druker: Oregon Health & Science University Knight Cancer Institute
Jeffrey W. Tyner: Oregon Health & Science University Knight Cancer Institute

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract FLT3 mutations are prevalent in AML patients and confer poor prognosis. Crenolanib, a potent type I pan-FLT3 inhibitor, is effective against both internal tandem duplications and resistance-conferring tyrosine kinase domain mutations. While crenolanib monotherapy has demonstrated clinical benefit in heavily pretreated relapsed/refractory AML patients, responses are transient and relapse eventually occurs. Here, to investigate the mechanisms of crenolanib resistance, we perform whole exome sequencing of AML patient samples before and after crenolanib treatment. Unlike other FLT3 inhibitors, crenolanib does not induce FLT3 secondary mutations, and mutations of the FLT3 gatekeeper residue are infrequent. Instead, mutations of NRAS and IDH2 arise, mostly as FLT3-independent subclones, while TET2 and IDH1 predominantly co-occur with FLT3-mutant clones and are enriched in crenolanib poor-responders. The remaining patients exhibit post-crenolanib expansion of mutations associated with epigenetic regulators, transcription factors, and cohesion factors, suggesting diverse genetic/epigenetic mechanisms of crenolanib resistance. Drug combinations in experimental models restore crenolanib sensitivity.

Date: 2019
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DOI: 10.1038/s41467-018-08263-x

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