Inhibition of p38-MK2 pathway enhances the efficacy of microtubule inhibitors in breast cancer cells

• DOI: 10.7554/elife.104859
• Publication Date: 2024-12-04T15:25:28Z
• Authors: Yu-Chia Chen; Mamoru Takada; Aerica Nagornyuk; Wu Muhan; Hideyuki Yamada; Takeshi Nagashima; Masayuki Ohtsuka; Jennifer G DeLuca; Steven Markus; Motoki Takaku; Aussie Suzuki

Microtubule-targeting agents (MTAs) have been successfully translated from basic research into clinical therapies and widely used as first- second-line chemotherapy drugs for various cancers. However, current MTAs exhibit positive responses only in subsets of patients are often accompanied by side effects due to their impact on normal cells. This underscores an urgent need develop novel therapeutic strategies that enhance MTA efficacy while minimizing toxicity tissues. In this study, we demonstrate inhibition the p38-MK2 (MAP kinase-activated protein kinase 2) pathway sensitizes cancer cells treatment. We utilize CMPD1, a dual-target inhibitor, concurrently suppress microtubule dynamicity. addition established role MK2 find CMPD1 rapidly induces depolymerization, preferentially at plus-end, leading tumor growth cell invasion both vitro vivo models. Notably, 10 nM is sufficient induce irreversible mitotic defects cells, but not non-transformed RPE1 highlighting its high specificity further validate specific inhibitor significantly potentiates sub-clinical concentrations MTA. summary, our findings suggest presents promising target combination with