title: Concurrent loss of the PTEN and RB1 tumor suppressors attenuates RAF dependence in melanomas harboring (V600E)BRAF.
abstract: Identifying the spectrum of genetic alterations that cooperate with critical oncogenes to promote transformation provides a foundation for understanding the diversity of clinical phenotypes observed in human cancers. Here, we performed integrated analyses to identify genomic alterations that co-occur with oncogenic BRAF in melanoma and abrogate cellular dependence upon this oncogene. We identified concurrent mutational inactivation of the PTEN and RB1 tumor suppressors as a mechanism for loss of BRAF/MEK dependence in melanomas harboring (V600E)BRAF mutations. RB1 alterations were mutually exclusive with loss of p16(INK4A), suggesting that whereas p16(INK4A) and RB1 may have overlapping roles in preventing tumor formation, tumors with loss of RB1 exhibit diminished dependence upon BRAF signaling for cell proliferation. These findings provide a genetic basis for the heterogeneity of clinical outcomes in patients treated with targeted inhibitors of the mitogen-activated protein kinase pathway. Our results also suggest a need for comprehensive screening for RB1 and PTEN inactivation in patients treated with RAF and MEK-selective inhibitors to determine whether these alterations are associated with diminished clinical benefit in patients whose cancers harbor mutant BRAF.
authors: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors: F
authors: F
authors: Xing
authors: Y
authors: Y
authors: Persaud
authors: C A
authors: CA
authors: Pratilas
authors: B S
authors: BS
authors: Taylor
authors: M
authors: M
authors: Janakiraman
authors: Q-B
authors: QB
authors: She
authors: H
authors: H
authors: Gallardo
authors: C
authors: C
authors: Liu
authors: T
authors: T
authors: Merghoub
authors: B
authors: B
authors: Hefter
authors: I
authors: I
authors: Dolgalev
authors: A
authors: A
authors: Viale
authors: A
authors: A
authors: Heguy
authors: E
authors: E
authors: De Stanchina
authors: D
authors: D
authors: Cobrinik
authors: G
authors: G
authors: Bollag
authors: J
authors: J
authors: Wolchok
authors: A
authors: A
authors: Houghton
authors: D B
authors: DB
authors: Solit
mesh_terms: D000818:Animals; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D016160:Retinoblastoma Protein / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D048490:raf Kinases / Q000502:physiology*
chemical_list: D000081082:Phosphoinositide-3 Kinase Inhibitors; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D048490:raf Kinases; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human