Inhibition of the MNK1/2-eIF4E Axis Augments Palbociclib-Mediated Antitumor Activity in Melanoma and Breast Cancer.

Autor:	Prabhu SA; Lady Davis Institute, Jewish General Hospital, Montréal, Québec, Canada.; Division of Experimental Medicine, McGill University, Montréal, Québec, Canada., Moussa O; Lady Davis Institute, Jewish General Hospital, Montréal, Québec, Canada.; Division of Experimental Medicine, McGill University, Montréal, Québec, Canada., Gonçalves C; Lady Davis Institute, Jewish General Hospital, Montréal, Québec, Canada., LaPierre JH; Lady Davis Institute, Jewish General Hospital, Montréal, Québec, Canada.; Division of Experimental Medicine, McGill University, Montréal, Québec, Canada., Chou H; Lady Davis Institute, Jewish General Hospital, Montréal, Québec, Canada., Huang F; Lady Davis Institute, Jewish General Hospital, Montréal, Québec, Canada.; Division of Experimental Medicine, McGill University, Montréal, Québec, Canada., Richard VR; Segal Cancer Proteomics Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada., Ferruzo PYM; Centre de recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, Québec, Canada.; Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, Québec, Canada., Guettler EM; Lady Davis Institute, Jewish General Hospital, Montréal, Québec, Canada., Soria-Bretones I; Lady Davis Institute, Jewish General Hospital, Montréal, Québec, Canada.; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada., Kirby L; Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Gagnon N; Lady Davis Institute, Jewish General Hospital, Montréal, Québec, Canada., Su J; Lady Davis Institute, Jewish General Hospital, Montréal, Québec, Canada., Silvester J; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada., Krisna SS; Lady Davis Institute, Jewish General Hospital, Montréal, Québec, Canada., Rose AAN; Lady Davis Institute, Jewish General Hospital, Montréal, Québec, Canada.; Division of Experimental Medicine, McGill University, Montréal, Québec, Canada.; Gerald Bronfman Department of Oncology, McGill University, Montréal, Québec, Canada., Sheppard KE; Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia., Cescon DW; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.; University of Toronto, Toronto, Ontario, Canada., Mallette FA; Centre de recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, Québec, Canada.; Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, Québec, Canada.; Department of Medicine, Université de Montréal, Montréal, Québec, Canada., Zahedi RP; Segal Cancer Proteomics Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada.; McGill Centre for Translational Research in Cancer, McGill University, Montréal, Québec, Canada., Borchers CH; Segal Cancer Proteomics Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada.; Gerald Bronfman Department of Oncology, McGill University, Montréal, Québec, Canada.; McGill Centre for Translational Research in Cancer, McGill University, Montréal, Québec, Canada., Del Rincon SV; Lady Davis Institute, Jewish General Hospital, Montréal, Québec, Canada.; Division of Experimental Medicine, McGill University, Montréal, Québec, Canada.; McGill Centre for Translational Research in Cancer, McGill University, Montréal, Québec, Canada., Miller WH; Lady Davis Institute, Jewish General Hospital, Montréal, Québec, Canada.; Division of Experimental Medicine, McGill University, Montréal, Québec, Canada.; McGill Centre for Translational Research in Cancer, McGill University, Montréal, Québec, Canada.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2023 Feb 01; Vol. 22 (2), pp. 192-204.
DOI:	10.1158/1535-7163.MCT-22-0092
Abstrakt:	Aberrant cell-cycle progression is characteristic of melanoma, and CDK4/6 inhibitors, such as palbociclib, are currently being tested for efficacy in this disease. Despite the promising nature of CDK4/6 inhibitors, their use as single agents in melanoma has shown limited clinical benefit. Herein, we discovered that treatment of tumor cells with palbociclib induces the phosphorylation of the mRNA translation initiation factor eIF4E. When phosphorylated, eIF4E specifically engenders the translation of mRNAs that code for proteins involved in cell survival. We hypothesized that cancer cells treated with palbociclib use upregulated phosphorylated eIF4E (phospho-eIF4E) to escape the antitumor benefits of this drug. Indeed, we found that pharmacologic or genetic disruption of MNK1/2 activity, the only known kinases for eIF4E, enhanced the ability of palbociclib to decrease clonogenic outgrowth. Moreover, a quantitative proteomics analysis of melanoma cells treated with combined MNK1/2 and CDK4/6 inhibitors showed downregulation of proteins with critical roles in cell-cycle progression and mitosis, including AURKB, TPX2, and survivin. We also observed that palbociclib-resistant breast cancer cells have higher basal levels of phospho-eIF4E, and that treatment with MNK1/2 inhibitors sensitized these palbociclib-resistant cells to CDK4/6 inhibition. In vivo we demonstrate that the combination of MNK1/2 and CDK4/6 inhibition significantly increases the overall survival of mice compared with either monotherapy. Overall, our data support MNK1/2 inhibitors as promising drugs to potentiate the antineoplastic effects of palbociclib and overcome therapy-resistant disease. (©2022 American Association for Cancer Research.)
Databáze:	MEDLINE
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