Nat Med. 2012 Sep 16;18(10):1503-10. doi: 10.1038/nm.2941. Epub 2012 Sep 16.
Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma.
Kwong LN, Costello JC, Liu H, Jiang S, Helms TL, Langsdorf AE, Jakubosky D, Genovese G, Muller FL, Jeong JH, Bender RP, Chu GC, Flaherty KT, Wargo JA, Collins JJ, Chin L.
1] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
The discovery of potent inhibitors of the BRAF proto-oncogene has revolutionized therapy for melanoma harboring mutations in BRAF, yet NRAS-mutant melanoma remains without an effective therapy. Because direct pharmacological inhibition of the RAS proto-oncogene has thus far been unsuccessful, we explored systems biology approaches to identify synergistic drug combination(s) that can mimic RAS inhibition. Here, leveraging an inducible mouse model of NRAS-mutant melanoma, we show that pharmacological inhibition of mitogen-activated protein kinase kinase (MEK) activates apoptosis but not cell-cycle arrest, which is in contrast to complete genetic neuroblastoma RAS homolog (NRAS) extinction, which triggers both of these effects. Network modeling pinpointed cyclin-dependent kinase 4 (CDK4) as a key driver of this differential phenotype. Accordingly, combined pharmacological inhibition of MEK and CDK4 in vivo led to substantial synergy in therapeutic efficacy. We suggest a gradient model of oncogenic NRAS signaling in which the output is gated, resulting in the decoupling of discrete downstream biological phenotypes as a result of incomplete inhibition. Such a gated signaling model offers a new framework to identify nonobvious coextinction target(s) for combined pharmacological inhibition in NRAS-mutant melanomas.
J Natl Cancer Inst. 2012 Sep 20. [Epub ahead of print]
Dual Suppression of the Cyclin-Dependent Kinase Inhibitors CDKN2C and CDKN1A in Human Melanoma.
Jalili A, Wagner C, Pashenkov M, Pathria G, Mertz KD, Widlund HR, Lupien M, Brunet JP, Golub TR, Stingl G, Fisher DE, Ramaswamy S, Wagner SN.
Affiliations of authors: Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna (AJ, CW, GP, KDM, GS, SNW) and CeMM-Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria (SNW); Laboratory of Clinical Immunology, National Research Center Institute of Immunology, Federal Medical and Biological Agency, Moscow, Russia (MP); Department of Pediatric Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital and Department of Dermatology, Harvard Medical School, Boston, MA (HRW); Department of Genetics, Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, NH (ML); The Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA (JPB, TRG, SR); Department of Pediatric Oncology and Center for Genome Discovery, Dana-Farber Cancer Institute, Boston, MA (TRG); Howard Hughes Medical Institute, Chevy Chase, MD (TRG); Department of Dermatology, Cutaneous Biology Research Center, Melanoma Program in Medical Oncology, Harvard Medical School, Boston, MA (DEF); Massachusetts General Hospital Cancer Center, Boston, MA (SR); Harvard Stem Cell Institute, Cambridge, MA (SR).
Resistance to BRAF(V600E) inhibitors is associated with reactivation of mitogen-activated protein kinase (MAPK) signaling at different levels in melanoma. To identify downstream effectors of MAPK signaling that could be used as potential additional therapeutic targets for BRAF(V600E) inhibitors, we used hTERT/CDK4R24C/p53DD-immortalized primary human melanocytes genetically modified to ectopically express BRAF ( V600E ) or NRAS ( G12D ) and observed induction of the AP-1 transcription factor family member c-Jun. Using a dominant negative approach, in vitro cell proliferation assays, western blots, and flow cytometry showed that MAPK signaling via BRAF(V600E) promotes melanoma cell proliferation at G1 through AP-1-mediated negative regulation of the INK4 family member, cyclin-dependent kinase inhibitor 2C (CDKN2C), and the CIP/KIP family member, cyclin-dependent kinase inhibitor 1A (CDKN1A). These effects were antagonized by pharmacological inhibition of CDKN2C and CDKN1A targets CDK2 and CDK4 in vitro. In contrast to BRAF ( V600E ) or NRAS ( G12D )-expressing melanocytes, melanoma cells have an inherent resistance to suppression of AP-1 activity by BRAF(V600E)- or MEK-inhibitors. Here, CDK2/4 inhibition statistically significantly augmented the effects of BRAF(V600E)- or MEK-inhibitors on melanoma cell viability in vitro and growth in athymic nude Foxn1 ( nu ) mice (P = .03 when mean tumor volume at day 13 was compared for BRAF(V600E) inhibitor vs BRAF(V600E) inhibitor plus CDK2/4 inhibition; P = .02 when mean tumor volume was compared for MEK inhibitor vs MEK inhibitor plus CDK2/4 inhibition; P values were calculated by a two-sided Welch t test; n = 4-8 mice per group).
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