Targeting RRM2 and Mutant BRAF Is a Novel Combinatorial Strategy for Melanoma.
The majority of patients with melanoma harbor mutations in the BRAF oncogene, thus making it a clinically relevant target. However, response to mutant BRAF inhibitors (BRAFi) is relatively short-lived with progression-free survival of only 6 to 7 months. Previously, we reported high expression of ribonucleotide reductase M2 (RRM2), which is rate-limiting for de novo dNTP synthesis, as a poor prognostic factor in patients with mutant BRAF melanoma. In this study, the notion that targeting de novo dNTP synthesis through knockdown of RRM2 could prolong the response of melanoma cells to BRAFi was investigated. Knockdown of RRM2 in combination with the mutant BRAFi PLX4720 (an analog of the FDA-approved drug vemurafenib) inhibited melanoma cell proliferation to a greater extent than either treatment alone. This occurred in vitro in multiple mutant BRAF cell lines and in a novel patient-derived xenograft (PDX) model system. Mechanistically, the combination increased DNA damage accumulation, which correlated with a global decrease in DNA damage repair (DDR) gene expression and increased apoptotic markers. After discontinuing PLX4720 treatment, cells showed marked recurrence. However, knockdown of RRM2 attenuated this rebound growth both in vitro and in vivo, which correlated with maintenance of the senescence-associated cell-cycle arrest.



Inhibition of RRM2 converts the transient response of melanoma cells to BRAFi to a stable response and may be a novel combinatorial strategy to prolong therapeutic response of patients with melanoma. Mol Cancer Res; 14(9); 767-75. ©2016 AACR.
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, Pennsylvania. Kazan Federal University, Kazan, Russia.
Nail
N
Fatkhutdinov
Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania.
Katrin
K
Sproesser
Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania.
Clemens
C
Krepler
Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania.
Qin
Q
Liu
Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania.
Patricia A
PA
Brafford
Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania.
Meenhard
M
Herlyn
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, Pennsylvania. kaird@wistar.org rzhang@wistar.org.
Katherine M
KM
Aird
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, Pennsylvania.
Rugang
R
Zhang
D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008545:Melanoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D011897:Random Allocation; D012262:Ribonucleoside Diphosphate Reductase / Q000172:deficiency / Q000235:genetics*; D013449:Sulfonamides / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D007211:Indoles; C528407:PLX 4720; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; C093713:ribonucleotide reductase M2; D012262:Ribonucleoside Diphosphate Reductase; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf