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

by Selleckchem | Jul 26 2023

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.

Comments:

The study you mentioned evaluated the potential of eFT508, a highly selective inhibitor of MNK1/2 (MAPK-interacting kinases 1 and 2), as a therapeutic option for osteosarcoma. Osteosarcoma is a type of cancer that primarily affects the bone and has limited treatment options. The researchers aimed to assess the efficacy of eFT508 as a single agent and in combination with paclitaxel in preclinical models of osteosarcoma.

The results of the study demonstrated that eFT508 exhibited activity against multiple osteosarcoma cell lines. It effectively inhibited the growth, survival, and migration of these cancer cells. Importantly, eFT508 demonstrated selectivity for osteosarcoma cells, showing significantly less toxicity towards normal osteoblastic cells.

In animal models, eFT508, when administered at a non-toxic dose, effectively halted tumor growth throughout the entire duration of treatment. This suggests its potential as a therapeutic agent for osteosarcoma. Mechanistically, eFT508 was found to inhibit the phosphorylation of eIF4E (eukaryotic translation initiation factor 4E) and subsequent protein translation mediated by eIF4E.

Furthermore, the study explored the combination of eFT508 and paclitaxel in osteosarcoma cells. The combination was found to be synergistic, as indicated by the combination index. This implies that the two drugs acted together more effectively than either drug alone in inhibiting the growth of osteosarcoma cells.

Overall, the findings of this study suggest that MNK1/2 inhibition, particularly with eFT508, holds promise as a therapeutic strategy for osteosarcoma. The selective targeting of osteosarcoma cells and the synergistic effect observed when combined with paclitaxel provide further support for the potential of eFT508 as a candidate for the treatment of osteosarcoma.