MELK controls tumor metabolism to promote resistance to melanoma therapy

ABSTRACT Melanoma is the most aggressive form of skin cancer, and despite major advances in targeted and immune therapies, durable responses remain limited due to the emergence of resistance mechanisms. Metabolic reprogramming has emerged as a key driver of therapy resistance, allowing tumor cells to adapt to environmental and therapeutic pressures. Here, we identify the maternal embryonic leucine zipper kinase (MELK) as a critical mediator of resistance in melanoma. We demonstrate that MELK stimulates intracellular accumulation of amino acids, leading to activation of mTORC1 signaling and enhanced mitochondrial metabolism and biogenesis. This metabolic shift promotes resistance to immune checkpoint blockade. Importantly, preclinical MELK inhibition sensitizes resistant melanoma cells to immunotherapy, revealing a potential combinatorial strategy to overcome resistance. Our findings establish MELK as a central regulator of metabolic adaptation and therapeutic resistance in melanoma, highlighting its potential as a promising therapeutic target. Competing Interest Statement T.P. received consulting honoraria from Almirall, AbbVie, BMS, Incyte, Janssen, Lilly, Novartis, Pfizer, UCB and Vyne Therapeutics; has received grants or honoraria from Almirall, AbbVie, Amgen, BMS, Celgene, Galderma, GSK, Incyte, Janssen, LEO Pharma, Lilly, MSD, Novartis, Pfizer, Sanofi, SUN Pharma, Takeda and UCB; C.R. received consulting fees from BMS, Roche, Pierre Fabre, Novartis, Sanofi, Pfizer, MSD, Merck, Sunpharma, Ultimovacs, Regeneron, Egle, Philogen, MAAT Pharma, IO Biotech; payment honoraria from Pierre Fabre, Sanofi, BMS, MSD, Novartis; supporting for attending meetings from Pierre Fabre, participation on advisory board from BMS, Roche, Pierre Fabre, Novartis, Sanofi, Pfizer, MSD, Merck, Sunpharma, Ultimovacs, Regeneron, EGLE, Philogen, MAAT Pharma. All the other authors declare no conflict of interest.