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Ref Type Journal Article
PMID (31088841)
Authors McMahon CM, Ferng T, Canaani J, Wang ES, Morrissette JJD, Eastburn DJ, Pellegrino M, Durruthy-Durruthy R, Watt CD, Asthana S, Lasater EA, DeFilippis R, Peretz CAC, McGary LHF, Deihimi S, Logan AC, Luger SM, Shah NP, Carroll M, Smith CC, Perl AE
Title Clonal Selection with RAS Pathway Activation Mediates Secondary Clinical Resistance to Selective FLT3 Inhibition in Acute Myeloid Leukemia.
URL
Abstract Text Gilteritinib is a potent and selective FLT3 kinase inhibitor with single-agent clinical efficacy in relapsed/refractory FLT3-mutated acute myeloid leukemia (AML). In this context, however, gilteritinib is not curative, and response duration is limited by the development of secondary resistance. To evaluate resistance mechanisms, we analyzed baseline and progression samples from patients treated on clinical trials of gilteritinib. Targeted next-generation sequencing at the time of AML progression on gilteritinib identified treatment-emergent mutations that activate RAS/MAPK pathway signaling, most commonly in NRAS or KRAS. Less frequently, secondary FLT3-F691L gatekeeper mutations or BCR-ABL1 fusions were identified at progression. Single-cell targeted DNA sequencing revealed diverse patterns of clonal selection and evolution in response to FLT3 inhibition, including the emergence of RAS mutations in FLT3-mutated subclones, the expansion of alternative wild-type FLT3 subclones, or both patterns simultaneously. These data illustrate dynamic and complex changes in clonal architecture underlying response and resistance to mutation-selective tyrosine kinase inhibitor therapy in AML. SIGNIFICANCE: Comprehensive serial genotyping of AML specimens from patients treated with the selective FLT3 inhibitor gilteritinib demonstrates that complex, heterogeneous patterns of clonal selection and evolution mediate clinical resistance to tyrosine kinase inhibition in FLT3-mutated AML. Our data support the development of combinatorial targeted therapeutic approaches for advanced AML.See related commentary by Wei and Roberts, p. 998.This article is highlighted in the In This Issue feature, p. 983.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
CBL Q367_E373delinsRLK indel unknown CBL Q367_E373delinsRLK results in a deletion of seven amino acids in the linker region of the Cbl protein from amino acids 367 to 373, combined with the insertion of an arginine (R), a leucine (L), and a lysine (K) at the same site (UniProt.org). Q367_E373delinsRLK has been identified in the scientific literature (PMID: 31088841), but has not been biochemically characterized and therefore, its effect on CBl protein function is unknown (PubMed, Jan 2024).
FLT3 C35S missense unknown FLT3 C35S lies within the extracellular domain of the Flt3 protein (UniProt.org). C35S has been identified in the scientific literature (PMID: 31088841), but has not been biochemically characterized and therefore, its effect on Flt3 protein function is unknown (PubMed, Jan 2024).
FLT3 M837K missense unknown FLT3 M837K lies within the protein kinase domain of the Flt3 protein (UniProt.org). M837K has been identified in the scientific literature (PMID: 32040554, PMID: 31088841), but has not been biochemically characterized and therefore, its effect on Flt3 protein function is unknown (PubMed, Jan 2024).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FLT3 exon 14 ins FLT3 C35S hematologic cancer sensitive Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, Xospata (gilteritinib) inhibited growth of transformed hematologic cells expressing FLT3-ITD and FLT3 C35S in culture (PMID: 31088841). 31088841
FLT3 exon 14 ins FLT3 M837K hematologic cancer sensitive Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, Xospata (gilteritinib) inhibited growth of transformed hematologic cells expressing FLT3-ITD and FLT3 M837K in culture (PMID: 31088841). 31088841
FLT3 exon 14 ins NRAS Q61K acute myeloid leukemia resistant Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, acute myeloid leukemia cells harboring FLT3-ITD and NRAS Q61K were resistant to Xospata (gilteritinib) as demonstrated by increased cell growth and RAS/MAPK pathway activation in culture (PMID: 31088841). 31088841
FLT3 exon 14 ins FLT3 D835X NRAS G13D acute myeloid leukemia predicted - resistant Gilteritinib Case Reports/Case Series Actionable In a clinical study, a patient with acute myeloid leukemia harboring FLT3-ITD and a D835 mutation progressed on Xospata (gilteritinib) treatment and was found to have acquired NRAS G13D (PMID: 31088841). 31088841
FLT3 exon 14 ins FLT3 D835X NRAS Q61H acute myeloid leukemia predicted - resistant Gilteritinib Case Reports/Case Series Actionable In a clinical study, a patient with acute myeloid leukemia harboring FLT3-ITD and a D835 mutation progressed on Xospata (gilteritinib) treatment and was found to have acquired NRAS Q61H (PMID: 31088841). 31088841
CBL Q367_E373delinsRLK FLT3 exon 14 ins FLT3 D835X NRAS G12D acute myeloid leukemia predicted - resistant Gilteritinib Case Reports/Case Series Actionable In a clinical study, a patient with acute myeloid leukemia harboring FLT3-ITD and a D835 mutation progressed on Xospata (gilteritinib) treatment and was found to have acquired NRAS G12D and CBL Q367_E373delinsRLK (PMID: 31088841). 31088841
FLT3 exon 14 ins NRAS G12C acute myeloid leukemia resistant Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, acute myeloid leukemia cells harboring FLT3-ITD and NRAS G12C were resistant to Xospata (gilteritinib) as demonstrated by increased cell growth and RAS/MAPK pathway activation in culture (PMID: 31088841). 31088841
FLT3 exon 14 ins NRAS G12C acute myeloid leukemia sensitive Gilteritinib + Trametinib Preclinical - Cell culture Actionable In a preclinical study, the combination of Xospata (gilteritinib) and Mekinist (trametinib) inhibited cell growth in acute myeloid leukemia cells harboring FLT3-ITD and NRAS G12C in culture (PMID: 31088841). 31088841
FLT3 exon 14 ins NRAS Q61K acute myeloid leukemia sensitive Gilteritinib + Trametinib Preclinical - Cell culture Actionable In a preclinical study, the combination of Xospata (gilteritinib) and Mekinist (trametinib) inhibited cell growth in acute myeloid leukemia cells harboring FLT3-ITD and NRAS Q61K in culture (PMID: 31088841). 31088841
FLT3 exon 14 ins FLT3 D835X NRAS G13C NRAS G13R acute myeloid leukemia predicted - resistant Gilteritinib Case Reports/Case Series Actionable In a clinical study, a patient with acute myeloid leukemia harboring FLT3-ITD and a D835 mutation progressed on Xospata (gilteritinib) treatment and was found to have acquired NRAS G13C and G13R (PMID: 31088841). 31088841
FLT3 exon 14 ins FLT3 D835X NRAS G13R acute myeloid leukemia predicted - resistant Gilteritinib Case Reports/Case Series Actionable In a clinical study, two patients with acute myeloid leukemia harboring FLT3-ITD and a D835 mutation progressed on Xospata (gilteritinib) treatment and were found to have acquired NRAS G13R (PMID: 31088841). 31088841
FLT3 exon 14 ins FLT3 F691L FLT3 D835X acute myeloid leukemia predicted - resistant Gilteritinib Case Reports/Case Series Actionable In a clinical study, four patients with acute myeloid leukemia harboring FLT3-ITD and a D835 mutation progressed on Xospata (gilteritinib) treatment and were found to have acquired FLT3 F691L (PMID: 31088841). 31088841
FLT3 exon 14 ins FLT3 D835X NRAS G12D NRAS G12S acute myeloid leukemia predicted - resistant Gilteritinib Case Reports/Case Series Actionable In a clinical study, a patient with acute myeloid leukemia harboring FLT3-ITD and a D835 mutation progressed on Xospata (gilteritinib) treatment and was found to have acquired NRAS G12S and G12D (PMID: 31088841). 31088841
FLT3 exon 14 ins FLT3 D835X NRAS Q61K acute myeloid leukemia predicted - resistant Gilteritinib Case Reports/Case Series Actionable In a clinical study, two patients with acute myeloid leukemia harboring FLT3-ITD and a D835 mutation progressed on Xospata (gilteritinib) treatment and were found to have acquired NRAS Q61K (PMID: 31088841). 31088841
BRAF G469A CBL C404Y FLT3 exon 14 ins FLT3 D835X acute myeloid leukemia predicted - resistant Gilteritinib Case Reports/Case Series Actionable In a clinical study, a patient with acute myeloid leukemia harboring FLT3-ITD and a D835 mutation progressed on Xospata (gilteritinib) treatment and was found to have acquired CBL C404Y and BRAF G469A (PMID: 31088841). 31088841
FLT3 exon 14 ins FLT3 D835X NRAS Q61R acute myeloid leukemia predicted - resistant Gilteritinib Case Reports/Case Series Actionable In a clinical study, a patient with acute myeloid leukemia harboring FLT3-ITD and a D835 mutation progressed on Xospata (gilteritinib) treatment and was found to have acquired NRAS Q61R in addition to WT1 L378Pfs*6 (PMID: 31088841). 31088841