MAPK-interacting kinases inhibition by eFT508 overcomes chemoresistance in preclinical model of osteosarcoma

Abstract

The MAPK-interacting kinases 1 and 2 (MNK1/2) have generated increasing interest as therapeutic targets for many cancers with little known in osteosarcoma. This study evaluated the efficacy of eFT508, a highly selective inhibitor of MNK1/2, as single drug alone and in combination with paclitaxel in preclinical models of osteosarcoma. EFT508 is active against multiple osteosarcoma cell lines via inhibiting growth, survival and migration. It also demonstrates anti-osteosarcoma selectivity with much less toxicity on normal osteoblastic than osteosarcoma cells. Consistent with in vitro findings, eFT508 at non-toxic dose significantly arrested tumor growth in mice throughout the whole duration of treatment. Mechanistically, eEFT508 is highly effective in blocking eIF4E phosphorylation and eIF4E-mediated protein translation. Combination index shows that eFT508 and paclitaxel is synergistic in osteosarcoma cells. Our findings highlight the therapeutic value of MNK1/2 inhibition and suggest eFT508 as a promising candidate for the treatment of osteosarcoma.

Inhibition of MNK pathway sensitizes nasopharyngeal carcinoma to radiotherapy

“…Our results showed that eFT508, a potent inhibitor of MNK1 and MNK2 with IC50 values in the low nanomolar range [21], does not cause general toxicity in mice at an effective dose. The anti-cancer activities of eFT508 have recently been revealed in osteosarcoma, leukemia, glioblastoma, and breast cancer, particularly its ability to overcome chemoresistance [22][23][24][25]. eFT508 has entered clinical trials for solid cancers, leukemia, and lymphoma (ClinicalTrials.…”