TY  - JOUR
AU  - Monfort-Vengut, Ana
AU  - Sanz-Gómez, Natalia
AU  - Ballesteros-Sánchez, Sandra
AU  - Ortigosa, Beatriz
AU  - Cambón, Aitana
AU  - Ramos, Maria
AU  - Lorenzo, Ángela Montes-San
AU  - Escribano-Cebrián, María
AU  - Rosa-Rosa, Juan Manuel
AU  - Martínez-López, Joaquín
AU  - Sánchez-Prieto, Ricardo
AU  - Sotillo, Rocío
AU  - de Cárcer, Guillermo
TI  - Osmotic stress influences microtubule drug response via WNK1 kinase signaling.
JO  - Drug resistance updates
VL  - 79
SN  - 1368-7646
CY  - Oxford
PB  - Elsevier
M1  - DKFZ-2025-00235
SP  - 101203
PY  - 2025
AB  - Ion homeostasis is critical for numerous cellular processes, and disturbances in ionic balance underlie diverse pathological conditions, including cancer progression. Targeting ion homeostasis is even considered as a strategy to treat cancer. However, very little is known about how ion homeostasis may influence anticancer drug response. In a genome-wide CRISPR-Cas9 resistance drug screen, we identified and validated the master osmostress regulator WNK1 kinase as a modulator of the response to the mitotic inhibitor rigosertib. Osmotic stress and WNK1 inactivation lead to an altered response not only to rigosertib treatment but also to other microtubule-related drugs, minimizing the prototypical mitotic arrest produced by these compounds. This effect is due to an alteration in microtubule stability and polymerization dynamics, likely maintained by fluctuations in intracellular molecular crowding upon WNK1 inactivation. This promotes resistance to microtubule depolymerizing compounds, and increased sensitivity to microtubule stabilizing drugs. In summary, our data proposes WNK1 osmoregulation activity as an important modulator for microtubule-associated chemotherapy response.
KW  - Microtubule dynamics (Other)
KW  - Mitosis (Other)
KW  - Osmotic stress (Other)
KW  - Rigosertib (Other)
KW  - WNK1 (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:39855050
DO  - DOI:10.1016/j.drup.2025.101203
UR  - https://inrepo02.dkfz.de/record/298228
ER  -