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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 Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 27
Issue 14
Date 2021 Jul 15
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 D535Y following relapse on Turalio (pexidartinib) treatment (PMID: 34103301; NCT01349049). 34103301