Mutations in the RAS pathway as potential precision medicine targets in treatment of rhabdomyosarcoma.
Precision medicine strategies for treating rhabdomyosarcoma (RMS), a childhood malignancy, have not been developed. We examined the effect of CH5126766, a potent selective dual RAF/MEK inhibitor, on RMS cell lines. Among the eleven cell lines studied, one NRAS and two HRAS mutated cell lines were detected. CH5126766 inhibited the proliferation and growth in all of the RAS-mutated RMS cell lines, while it induced G1 cell cycle arrest in two of them. G1 cell cycle arrest was accompanied by p21 up-regulation and RB dephosphorylation. CH5126766 also suppressed the in vivo growth of RAS-mutated RMS tumor, and the mice showed improved survival. Thus, our results demonstrate that CH5126766 is an effective RAF/MEK inhibitor in RAS-mutated RMS. This study not only shows that in RMS, mutations in the RAS pathway can be a target for precision medicine, but also demonstrates that the evaluation of the gene mutation status is important in childhood malignancies.
['Nakagawa|Norio|N|', 'Kikuchi|Ken|K|', 'Yagyu|Shigeki|S|', 'Miyachi|Mitsuru|M|', 'Iehara|Tomoko|T|', 'Tajiri|Tatsuro|T|', 'Sakai|Toshiyuki|T|', 'Hosoi|Hajime|H|']
D000818:Animals D002453:Cell Cycle D045744:Cell Line, Tumor D002648:Child D003374:Coumarins D005260:Female D006801:Humans D008807:Mice, Inbred BALB C D008819:Mice, Nude D009154:Mutation D057285:Precision Medicine D047428:Protein Kinase Inhibitors D012208:Rhabdomyosarcoma D015398:Signal Transduction D018631:ras Proteins
Precision medicine Rhabdomyosarcoma MEK inhibitor Cell cycle RAS mutation