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Mutation of NRAS but not KRAS significantly reduces myeloma sensitivity to single-agent bortezomib therapy.

Authors: Mulligan, G  Lichter, DI  Di Bacco, A  Blakemore, SJ  Berger, A  Koenig, E  Bernard, H  Trepicchio, W  Li, B  Neuwirth, R  Chattopadhyay, N  Bolen, JB  Dorner, AJ  Van de Velde, H  Ricci, D  Jagannath, S  Berenson, JR  Richardson, PG  Stadtmauer, EA  Orlowski, RZ  Lonial, S  Anderson, KC  Sonneveld, P  San Miguel, JF  Esseltine, DL  Schu, M 
Citation: Mulligan G, etal., Blood. 2014 Jan 30;123(5):632-9. doi: 10.1182/blood-2013-05-504340. Epub 2013 Dec 11.
Pubmed: (View Article at PubMed) PMID:24335104
DOI: Full-text: DOI:10.1182/blood-2013-05-504340

Various translocations and mutations have been identified in myeloma, and certain aberrations, such as t(4;14) and del17, are linked with disease prognosis. To investigate mutational prevalence in myeloma and associations between mutations and patient outcomes, we tested a panel of 41 known oncogenes and tumor suppressor genes in tumor samples from 133 relapsed myeloma patients participating in phase 2 or 3 clinical trials of bortezomib. DNA mutations were identified in 14 genes. BRAF as well as RAS genes were mutated in a large proportion of cases (45.9%) and these mutations were mutually exclusive. New recurrent mutations were also identified, including in the PDGFRA and JAK3 genes. NRAS mutations were associated with a significantly lower response rate to single-agent bortezomib (7% vs 53% in patients with mutant vs wild-type NRAS, P = .00116, Bonferroni-corrected P = .016), as well as shorter time to progression in bortezomib-treated patients (P = .0058, Bonferroni-corrected P = .012). However, NRAS mutation did not impact outcome in patients treated with high-dose dexamethasone. KRAS mutation did not reduce sensitivity to bortezomib or dexamethasone. These findings identify a significant clinical impact of NRAS mutation in myeloma and demonstrate a clear example of functional differences between the KRAS and NRAS oncogenes.

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CRRD Object Information
CRRD ID: 11535049
Created: 2016-09-20
Species: All species
Last Modified: 2016-09-20
Status: ACTIVE



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