Mutation of NRAS but not KRAS significantly reduces myeloma sensitivity to single-agent bortezomib therapy
Menée sur des échantillons tumoraux prélevés sur 133 patients atteints d'un myélome multiple récidivant et inclus dans un essai de phase II ou III, cette étude montre que des mutations du gène NRAS, et non des mutations du gène KRAS, modifient la sensibilité des cellules tumorales au bortézomib
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% versus 53% in patients with mutant versus 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.
Blood 2013