Rearrangements of the RAF kinase pathway in prostate cancer, gastric cancer and melanoma.
Although recurrent gene fusions involving erythroblastosis virus E26 transformation-specific (ETS) family transcription factors are common in prostate cancer, their products are considered 'undruggable' by conventional approaches. Recently, rare targetable gene fusions involving the anaplastic lymphoma receptor tyrosine kinase (ALK) gene, have been identified in 1-5% of lung cancers, suggesting that similar rare gene fusions may occur in other common epithelial cancers, including prostate cancer. Here we used paired-end transcriptome sequencing to screen ETS rearrangement-negative prostate cancers for targetable gene fusions and identified the SLC45A3-BRAF (solute carrier family 45, member 3-v-raf murine sarcoma viral oncogene homolog B1) and ESRP1-RAF1 (epithelial splicing regulatory protein-1-v-raf-1 murine leukemia viral oncogene homolog-1) gene fusions. Expression of SLC45A3-BRAF or ESRP1-RAF1 in prostate cells induced a neoplastic phenotype that was sensitive to RAF and mitogen-activated protein kinase kinase (MAP2K1) inhibitors. Screening a large cohort of patients, we found that, although rare, recurrent rearrangements in the RAF pathway tend to occur in advanced prostate cancers, gastric cancers and melanoma. Taken together, our results emphasize the key role of RAF family gene rearrangements in cancer, suggest that RAF and MEK inhibitors may be useful in a subset of gene fusion-harboring solid tumors and demonstrate that sequencing of tumor transcriptomes and genomes may lead to the identification of rare targetable fusions across cancer types.
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA.
Nallasivam
N
Palanisamy
Bushra
B
Ateeq
Shanker
S
Kalyana-Sundaram
Dorothee
D
Pflueger
Kalpana
K
Ramnarayanan
Sunita
S
Shankar
Bo
B
Han
Qi
Q
Cao
Xuhong
X
Cao
Khalid
K
Suleman
Chandan
C
Kumar-Sinha
Saravana M
SM
Dhanasekaran
Ying-bei
YB
Chen
Raquel
R
Esgueva
Samprit
S
Banerjee
Christopher J
CJ
LaFargue
Javed
J
Siddiqui
Francesca
F
Demichelis
Peter
P
Moeller
Tarek A
TA
Bismar
Rainer
R
Kuefer
Douglas R
DR
Fullen
Timothy M
TM
Johnson
Joel K
JK
Greenson
Thomas J
TJ
Giordano
Patrick
P
Tan
Scott A
SA
Tomlins
Sooryanarayana
S
Varambally
Mark A
MA
Rubin
Christopher A
CA
Maher
Arul M
AM
Chinnaiyan
D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics*; D026901:Membrane Transport Proteins / Q000235:genetics; D009004:Monosaccharide Transport Proteins; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics*; D014178:Translocation, Genetic
C539364:ESRP1 protein, human; D026901:Membrane Transport Proteins; D009004:Monosaccharide Transport Proteins; D015514:Oncogene Proteins, Fusion; D016601:RNA-Binding Proteins; C551031:SLC45a3 protein, human; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf