MEK inhibition preferentially suppresses anchorage-independent growth in osteosarcoma cells and decreases tumors in vivo

Takatsune Shimizu, Kiyomi Kimura, Eiji Sugihara, Sayaka Yamaguchi-Iwai, Hiroyuki Nobusue, Oltea Sampetrean, Yuji Otsuki, Yumi Fukuchi, Kaori Saitoh, Keiko Kato, Tomoyoshi Soga, Akihiro Muto, Hideyuki Saya

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)


Osteosarcoma is the most common high-grade malignancy of bone, and novel therapeutic options are urgently required. Previously, we developed mouse osteosarcoma AXT cells that can proliferate both under adherent and nonadherent conditions. Based on metabolite levels, nonadherent conditions were more similar to the in vivo environment than adherent conditions. A drug screen identified MEK inhibitors, including trametinib, that preferentially decreased the viability of nonadherent AXT cells. Trametinib inhibited the cell cycle and induced apoptosis in AXT cells, and both effects were stronger under nonadherent conditions. Trametinib also potently decreased viability in U2OS cells, but its effects were less prominent in MG63 or Saos2 cells. By contrast, MG63 and Saos2 cells were more sensitive to PI3K inhibition than AXT or U2OS cells. Notably, the combination of MAPK/ERK kinase (MEK) and PI3K inhibition synergistically decreased viability in U2OS and AXT cells, but this effect was less pronounced in MG63 or Saos2 cells. Therefore, signal dependence for cell survival and crosstalk between MEK–ERK and PI3K–AKT pathways in osteosarcoma are cell context-dependent. The activation status of other kinases including CREB varied in a cell context-dependent manner, which might determine the response to MEK inhibition. A single dose of trametinib was sufficient to decrease the size of the primary tumor and circulating tumor cells in vivo. Moreover, combined administration of trametinib and rapamycin or conventional anticancer drugs further increased antitumor activity. Thus, given optimal biomarkers for predicting its effects, trametinib holds therapeutic potential for the treatment of osteosarcoma.

Original languageEnglish
Pages (from-to)2732-2743
Number of pages12
JournalJournal of Orthopaedic Research
Issue number12
Publication statusPublished - 12-2021
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Orthopedics and Sports Medicine


Dive into the research topics of 'MEK inhibition preferentially suppresses anchorage-independent growth in osteosarcoma cells and decreases tumors in vivo'. Together they form a unique fingerprint.

Cite this