Recurrent mutations in cyclin D3 confer clinical resistance to FLT3 inhibitors in acute myeloid leukemia Journal Article
| Authors: | Smith, C. C.; Viny, A. D.; Massi, E.; Kandoth, C.; Socci, N. D.; Rapaport, F.; Najm, M.; Medina-Martinez, J. S.; Papaemmanuil, E.; Tarver, T. C.; Hsu, H. H.; Le, M. H.; West, B.; Bollag, G.; Taylor, B. S.; Levine, R. L.; Shah, N. P. |
| Article Title: | Recurrent mutations in cyclin D3 confer clinical resistance to FLT3 inhibitors in acute myeloid leukemia |
| Abstract: | Purpose: 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). Experimental Design: 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-ITDþ 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. Results: 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. Conclusions: 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. © 2021 American Association for Cancer Research. |
| Journal Title: | Clinical Cancer Research |
| Volume: | 27 |
| Issue: | 14 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2021-07-15 |
| Start Page: | 4003 |
| End Page: | 4011 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-20-3458 |
| PUBMED: | 34103301 |
| PROVIDER: | scopus |
| PMCID: | PMC8282743 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 August 2021 -- Source: Scopus |
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