title: Mutation of NRAS but not KRAS significantly reduces myeloma sensitivity to single-agent bortezomib therapy.
abstract: 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.
authors: Takeda Pharmaceuticals International Co., Cambridge, MA;
authors: George
authors: G
authors: Mulligan
authors: David I
authors: DI
authors: Lichter
authors: Alessandra
authors: A
authors: Di Bacco
authors: Stephen J
authors: SJ
authors: Blakemore
authors: Allison
authors: A
authors: Berger
authors: Erik
authors: E
authors: Koenig
authors: Hugues
authors: H
authors: Bernard
authors: William
authors: W
authors: Trepicchio
authors: Bin
authors: B
authors: Li
authors: Rachel
authors: R
authors: Neuwirth
authors: Nibedita
authors: N
authors: Chattopadhyay
authors: Joseph B
authors: JB
authors: Bolen
authors: Andrew J
authors: AJ
authors: Dorner
authors: Helgi
authors: H
authors: van de Velde
authors: Deborah
authors: D
authors: Ricci
authors: Sundar
authors: S
authors: Jagannath
authors: James R
authors: JR
authors: Berenson
authors: Paul G
authors: PG
authors: Richardson
authors: Edward A
authors: EA
authors: Stadtmauer
authors: Robert Z
authors: RZ
authors: Orlowski
authors: Sagar
authors: S
authors: Lonial
authors: Kenneth C
authors: KC
authors: Anderson
authors: Pieter
authors: P
authors: Sonneveld
authors: Jesús F
authors: JF
authors: San Miguel
authors: Dixie-Lee
authors: DL
authors: Esseltine
authors: Matthew
authors: M
authors: Schu
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D009101:Multiple Myeloma / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009154:Mutation; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D011719:Pyrazines / Q000627:therapeutic use*; D016019:Survival Analysis; D018631:ras Proteins / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; C117307:KRAS protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011719:Pyrazines; D000069286:Bortezomib; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins