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

• DOI: 10.1158/1535-7163.c.6543604.v1
• Publication Date: 2023-04-03T23:55:30Z
• Authors: Sathyen A. Prabhu; Omar Moussa; Christophe Gonçalves; Judith H. LaPierre; Hsiang Chou; Fan Huang; Vincent R. Richard; Pault Y. M. Ferruzo; Elizabeth M. Guet...; Isabel Soria-Bret...; Laura Kirby; Natascha Gagnon; Jie Su; Jennifer Silvester; Sai Sakktee Krisna; April A. N. Rose; Karen E. Sheppard; David W. Cescon; Frédérick A. Mall...; Rene P. Zahedi; Christoph H. Borc...; Sonia V. del Rincon; Wilson H. Miller
• Keywords: Palbociclib; EIF4E; Clonogenic assay

<div>Abstract<p>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 their use single agents melanoma has shown limited clinical benefit. Herein, we discovered that treatment tumor cells with palbociclib induces phosphorylation mRNA translation initiation factor eIF4E. When phosphorylated, eIF4E specifically engenders mRNAs code proteins involved cell survival. We hypothesized cancer treated upregulated phosphorylated (phospho-eIF4E) to escape antitumor benefits drug. Indeed, found pharmacologic or genetic disruption MNK1/2 activity, only known kinases eIF4E, enhanced ability decrease clonogenic outgrowth. Moreover, a quantitative proteomics analysis combined inhibitors showed downregulation critical roles mitosis, including AURKB, TPX2, survivin. also observed palbociclib-resistant breast have higher basal levels phospho-eIF4E, sensitized these inhibition. <i>In vivo</i> demonstrate combination inhibition significantly increases overall survival mice compared either monotherapy. Overall, our data support drugs potentiate antineoplastic effects overcome therapy-resistant disease.</p></div>