Rearrangements of the RAF kinase pathway in prostate cancer, gastric cancer and melanoma

Nallasivam Palanisamy, Bushra Ateeq, Shanker Kalyana-Sundaram, Dorothee Pflueger, Kalpana Ramnarayanan, Sunita Shankar, Bo Han, Qi Cao, Xuhong Cao, Khalid Suleman, Chandan Kumar-Sinha, Saravana M. Dhanasekaran, Ying Bei Chen, Raquel Esgueva, Samprit Banerjee, Christopher J. Lafargue, Javed Siddiqui, Francesca Demichelis, Peter Moeller, Tarek A. BismarRainer Kuefer, Douglas R. Fullen, Timothy M. Johnson, Joel K. Greenson, Thomas J. Giordano, Patrick Tan, Scott A. Tomlins, Sooryanarayana Varambally, Mark A. Rubin, Christopher A. Maher, Arul M. Chinnaiyan

Research output: Contribution to journalArticlepeer-review

414 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)793-798
Number of pages6
JournalNature Medicine
Issue number7
StatePublished - Jul 2010

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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