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 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 & 10 others Gautam Borthakur, Guillermo Garcia-Manero, Farhad Ravandi, Hagop M. Kantarjian, Jorge Cortes, Robert Collins, Daelynn R. Buelow, Sharyn D. Baker, Brian Druker, Jeffrey Tyner

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
Article number244
JournalNature Communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

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leukemias
mutations
Acute Myeloid Leukemia
Mutation
inhibitors
Epigenomics
transponders
sequencing
prognosis
cohesion
tyrosine
regulators
transient response
refractories
Exome
crenolanib
drugs
Drug Combinations
Transient analysis
Refractory materials

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms. / Zhang, Haijiao; Savage, Samantha; Schultz, Anna Reister; Bottomly, Daniel; White, Libbey; Segerdell, Erik; Wilmot, Beth; McWeeney, Shannon; Eide, Christopher A.; Nechiporuk, Tamilla; Carlos, Amy; Henson, Rachel; Lin, Chenwei; Searles, Robert; Ho, Hoang; Lam, Yee Ling; Sweat, Richard; Follit, Courtney; Jain, Vinay; Lind, Evan; Borthakur, Gautam; Garcia-Manero, Guillermo; Ravandi, Farhad; Kantarjian, Hagop M.; Cortes, Jorge; Collins, Robert; Buelow, Daelynn R.; Baker, Sharyn D.; Druker, Brian; Tyner, Jeffrey.

In: Nature Communications, Vol. 10, No. 1, 244, 01.12.2019.

Research output: Contribution to journalArticle

Zhang, H, Savage, S, Schultz, AR, Bottomly, D, White, L, Segerdell, E, Wilmot, B, McWeeney, S, Eide, CA, Nechiporuk, T, Carlos, A, Henson, R, Lin, C, Searles, R, Ho, H, Lam, YL, Sweat, R, Follit, C, Jain, V, Lind, E, Borthakur, G, Garcia-Manero, G, Ravandi, F, Kantarjian, HM, Cortes, J, Collins, R, Buelow, DR, Baker, SD, Druker, B & Tyner, J 2019, 'Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms', Nature Communications, vol. 10, no. 1, 244. https://doi.org/10.1038/s41467-018-08263-x
Zhang, Haijiao ; Savage, Samantha ; Schultz, Anna Reister ; Bottomly, Daniel ; White, Libbey ; Segerdell, Erik ; Wilmot, Beth ; McWeeney, Shannon ; Eide, Christopher A. ; Nechiporuk, Tamilla ; Carlos, Amy ; Henson, Rachel ; Lin, Chenwei ; Searles, Robert ; Ho, Hoang ; Lam, Yee Ling ; Sweat, Richard ; Follit, Courtney ; Jain, Vinay ; Lind, Evan ; Borthakur, Gautam ; Garcia-Manero, Guillermo ; Ravandi, Farhad ; Kantarjian, Hagop M. ; Cortes, Jorge ; Collins, Robert ; Buelow, Daelynn R. ; Baker, Sharyn D. ; Druker, Brian ; Tyner, Jeffrey. / Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms. In: Nature Communications. 2019 ; Vol. 10, No. 1.
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AU - Schultz, Anna Reister

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AU - White, Libbey

AU - Segerdell, Erik

AU - Wilmot, Beth

AU - McWeeney, Shannon

AU - Eide, Christopher A.

AU - Nechiporuk, Tamilla

AU - Carlos, Amy

AU - Henson, Rachel

AU - Lin, Chenwei

AU - Searles, Robert

AU - Ho, Hoang

AU - Lam, Yee Ling

AU - Sweat, Richard

AU - Follit, Courtney

AU - Jain, Vinay

AU - Lind, Evan

AU - Borthakur, Gautam

AU - Garcia-Manero, Guillermo

AU - Ravandi, Farhad

AU - Kantarjian, Hagop M.

AU - Cortes, Jorge

AU - Collins, Robert

AU - Buelow, Daelynn R.

AU - Baker, Sharyn D.

AU - Druker, Brian

AU - Tyner, Jeffrey

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N2 - 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.

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