Reference Detail

Ref Type

Journal Article

PMID

(34103301)

Authors

Smith CC, Viny AD, Massi E, Kandoth C, Socci ND, Rapaport F, Najm M, Medina-Martinez JS, Papaemmanuil E, Tarver TC, Hsu HH, Le MH, West B, Bollag G, Taylor BS, Levine RL, Shah NP

Title

Recurrent Mutations in Cyclin D3 Confer Clinical Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	27	14	2021 Jul 15	4003-4011	Clin Cancer Res

URL

Abstract Text

Biomarkers of response and resistance to FLT3 tyrosine kinase inhibitors (TKI) are still emerging, and optimal clinical combinations remain unclear. The purpose of this study is to identify co-occurring mutations that influence clinical response to the novel FLT3 inhibitor pexidartinib (PLX3397).We performed targeted sequencing of pretreatment blasts from 29 patients with FLT3 internal tandem duplication (ITD) mutations treated on the phase I/II trial of pexidartinib in relapsed/refractory FLT3-ITD+ acute myeloid leukemia (AML). We sequenced 37 samples from 29 patients with available material, including 8 responders and 21 non-responders treated at or above the recommended phase II dose of 3,000 mg.Consistent with other studies, we identified mutations in NRAS, TP53, IDH2, and a variety of epigenetic and transcriptional regulators only in non-responders. Among the most frequently mutated genes in non-responders was Cyclin D3 (CCND3). A total of 3 individual mutations in CCND3 (Q276*, S264R, and T283A) were identified in 2 of 21 non-responders (one patient had both Q276* and S264R). No CCND3 mutations were found in pexidartinib responders. Expression of the Q276* and T283A mutations in FLT3-ITD MV4;11 cells conferred resistance to apoptosis, decreased cell-cycle arrest, and increased proliferation in the presence of pexidartinib and other FLT3 inhibitors. Inhibition of CDK4/6 activity in CCND3 mutant MV4;11 cells restored pexidartinib-induced cell-cycle arrest but not apoptosis.Mutations in CCND3, a gene not commonly mutated in AML, are a novel cause of clinical primary resistance to FLT3 inhibitors in AML and may have sensitivity to CDK4/6 inhibition.

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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

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FLT3 exon 14 ins FLT3 N676K	acute myeloid leukemia	predicted - resistant	Pexidartinib	Case Reports/Case Series	Actionable	In a Phase I/II trial, an acute myeloid leukemia patient harboring a FLT3-ITD was found to have acquired FLT3 N676K following relapse on Turalio (pexidartinib) treatment (PMID: 34103301; NCT01349049).	34103301
FLT3 exon 14 ins FLT3 D835Y	acute myeloid leukemia	predicted - resistant	Pexidartinib	Case Reports/Case Series	Actionable	In a Phase I/II trial, an acute myeloid leukemia patient harboring a FLT3-ITD was found to have acquired FLT3 D835Y following relapse on Turalio (pexidartinib) treatment (PMID: 34103301; NCT01349049).	34103301