Research press release


Nature Medicine

Genetic rearrangements in cancer



A Chinnaiyanたちは、シーケンシング技術を利用して別のタイプの遺伝子再編成を探し、SLC45A3遺伝子とBRAF遺伝子の融合と、ESRP1遺伝子とRAF1遺伝子の融合を見つけ出した。これらの融合ではRAFファミリーに属するキナーゼが融合している。キナーゼは酵素の一種で、これまでの薬剤開発ではほかに比べてよい標的となっているため、Chinnaiyanたちは、このような再編成が存在する細胞が薬物治療に感受性を示すかどうかを調べた。実際に、前立腺細胞でこのような融合タンパク質が発現するとがんに似た特徴が現れるが、RAFキナーゼ阻害剤に対し感受性を示した。


The existence of genetic rearrangements that involve specific proteins in prostate cancer, gastric cancer and melanoma, is reported this week in Nature Medicine. The hybrid molecules resulting from these rearrangements could represent new therapeutic targets.

Genetic rearrangements that involve the fusion of transcription factors ― molecules that control gene expression ― have been commonly seen in cancer. However, pharmacologically targeting transcription factors is extremely challenging.

Arul Chinnaiyan and his colleagues used sequencing techniques to identify other types of gene rearrangements and identified fusions between the SLC45A3 and BRAF genes and between the ESRP1 and RAF1 genes. Since these fusions involve members of the RAF family of kinases ― type of enzymes ― and protein kinases have historically been better targets for drug development, the scientists explored if cells harboring the rearrangements would be susceptible to pharmacological treatments. Indeed, expression of these fusions in prostate cells induced a cancer-like characteristic that was sensitive to RAF kinase inhibitors.

Although rare, rearrangements in the RAF pathway tend to occur in advanced prostate cancers, gastric cancers and melanoma. Together, these results show that RAF inhibitors may be useful in a subset of tumors harboring gene fusions and demonstrate that sequencing of tumor genomes may lead to the identification of rare fusions across cancer types.

doi: 10.1038/nm.2166


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