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

Abstract

While recurrent gene fusions involving ETS family transcription factors are common in prostate cancer, their products are considered “undruggable” by conventional approaches. Recently, rare “targetable” gene fusions (involving the ALK kinase), have been identified in 1–5% of lung cancers1, suggesting that similar rare gene fusions may occur in other common epithelial cancers including prostate cancer. Here we employed paired-end transcriptome sequencing to screen ETS rearrangement negative prostate cancers for targetable gene fusions and identified the SLC45A3-BRAF and ESRP1-RAF1 gene fusions. Expression of SLC45A3-BRAF or ESRP1-RAF1 in prostate cells induced a neoplastic phenotype that was sensitive to RAF and MEK inhibitors. Screening a large cohort of patients, we found that although rare (1–2%), recurrent rearrangements in the RAF pathway tend to occur in advanced prostate cancers, gastric cancers, and melanoma. Taken together, our results emphasize the importance of RAF 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.

Frequent loss of RAF kinase inhibitor protein expression in acute myeloid leukemia

“…To further test for a possible involvement of RKIP in RAS driven transformation, we performed NIH3T3 transformation assays, a model frequently used to study the biology of oncogenic RAS. 29,30 RKIP significantly decreased focus formation induced by mutated RAS, suggesting synergistic effects of mutant RAS and loss of RKIP in cellular transformation. Importantly, as RKIP has proven unable to interact with RAS itself, 9 the effects on RAS driven transformation are most likely to be mediated via inhibition of the downstream effectors RAF/MEK.…”

“…To test for a functional synergism, we employed NIH3T3 cells, a well-established system to study RAS transformation. 29,30 Transfection of either HRAS V12 or KRAS V12 induced cellular transformation as assessed by the appearance of transformed cell foci, which were scored after 11 days of culture.…”

Elevated osteonectin/SPARC expression in primary prostate cancer predicts metastatic progression

“…[3][4][5][6][7][8] More recently, gene fusions involving androgenregulated promoters and ETS-related transcription factors or RAF kinases were discovered as promising CaP-specific bio-markers and therapeutic targets. 9,10 RAF fusions are present in about 2% of CaP associated with aggressive disease. 10 Earlier, other genes such as p53, [11][12][13] AR, 14,15 AKT/PTEN, 16 EZH2, 17 SPINK, 18 ETV1 9,19 have been shown to be associated with subsets of progressive CaP, however their use as prognostic markers in clinical setting needs to be streamlined.…”

“…9,10 RAF fusions are present in about 2% of CaP associated with aggressive disease. 10 Earlier, other genes such as p53, [11][12][13] AR, 14,15 AKT/PTEN, 16 EZH2, 17 SPINK, 18 ETV1 9,19 have been shown to be associated with subsets of progressive CaP, however their use as prognostic markers in clinical setting needs to be streamlined. SPARC (secreted protein, acidic, rich in cysteine) is a secreted glycoprotein that supports the migration of CaP cells to bone and demonstrates increased expression in CaP metastatic foci and cell lines.…”

Potential for targeted therapy in prostate cancers with ERG abnormalities

“…2,5 With regard to therapy, however, gene rearrangements involving transcription factors have unfortunately been largely considered poor targets for pharmacologic therapy, due to their lack of enzymatic activity, location within the nucleus and complex interaction with other proteins required for function. 13,14 Nonetheless, in a recent study by Brenner et al, 7 the authors identified a potential avenue of utility for poly(ADPribose) polymerase 1 (PARP1) inhibition in treatment and prognostication for patients with ETS-abnormal prostate cancer, opening the door for a wide spectrum of potential applications.…”