TY - JOUR
T1 - Mutation of NRAS but not KRAS significantly reduces myeloma sensitivity to single-agent bortezomib therapy
AU - Mulligan, George
AU - Lichter, David I.
AU - Bacco, Alessandra Di
AU - Blakemore, Stephen J.
AU - Berger, Allison
AU - Koenig, Erik
AU - Bernard, Hugues
AU - Trepicchio, William
AU - Li, Bin
AU - Neuwirth, Rachel
AU - Chattopadhyay, Nibedita
AU - Bolen, Joseph B.
AU - Dorner, Andrew J.
AU - Van De Velde, Helgi
AU - Ricci, Deborah
AU - Jagannath, Sundar
AU - Berenson, James R.
AU - Richardson, Paul G.
AU - Stadtmauer, Edward A.
AU - Orlowski, Robert Z.
AU - Lonial, Sagar
AU - Anderson, Kenneth C.
AU - Sonneveld, Pieter
AU - Miguel, Jeśus F.San
AU - Esseltine, Dixie Lee
AU - Schu, Matthew
PY - 2014/1/30
Y1 - 2014/1/30
N2 - 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 wildtype NRAS, P 5 .00116, Bonferroni-corrected P 5 .016), as well as shorter time to progression in bortezomib-treated patients (P 5 .0058, Bonferroni-corrected P 5 .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. 2014; 123(5):632-639).
AB - 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 wildtype NRAS, P 5 .00116, Bonferroni-corrected P 5 .016), as well as shorter time to progression in bortezomib-treated patients (P 5 .0058, Bonferroni-corrected P 5 .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. 2014; 123(5):632-639).
UR - https://www.scopus.com/pages/publications/84894041669
U2 - 10.1182/blood-2013-05-504340
DO - 10.1182/blood-2013-05-504340
M3 - Article
C2 - 24335104
AN - SCOPUS:84894041669
SN - 0006-4971
VL - 123
SP - 632
EP - 639
JO - Blood
JF - Blood
IS - 5
ER -