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Mutations in the RAS pathway as potential precision medicine targets in treatment of rhabdomyosarcoma

Author:
Nakagawa, Norio, Kikuchi, Ken, Yagyu, Shigeki, Miyachi, Mitsuru, Iehara, Tomoko, Tajiri, Tatsuro, Sakai, Toshiyuki, Hosoi, Hajime
Source:
Biochemical and biophysical research communications 2019 v.512 no.3 pp. 524-530
ISSN:
0006-291X
Subject:
cell cycle checkpoints, cell lines, childhood, dephosphorylation, genes, mice, mutation, neoplasms, precision medicine
Abstract:
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.
Agid:
6345309