Proteomic and phospho-proteomic longitudinal signatures of human skeletal muscle in lung cancer cachexia

ABSTRACT Weight loss is a potentially deadly hallmark of many cancers, including lung cancer. In particular, the loss of skeletal muscle mass and function impairs survival and lowers quality of life. Despite being a major determinant of prognosis, the molecular drivers of muscle wasting remain ill-defined. Therefore, there is a critical need for human molecular data to support the development of effective therapies for this currently untreatable condition. Here, we utilize cutting-edge proteomics technology to longitudinally map the proteome and phosphoproteome of skeletal muscle from patients with newly diagnosed, advanced-stage non-small cell lung cancer during their treatment. Leveraging deep in vivo clinical phenotyping of activity, body composition, muscle quality, and nutritional risk, we identified 118/174 muscle proteins/phospho-sites associated with cachexia at diagnosis with indications of sexual dimorphism. Treatment altered 278 proteins and 1,155 phospho-sites, of which 137/91 proteins/phospho-sites were associated with muscle wasting. Our findings highlight disrupted calcium, anabolic, and stress signalling, alongside extracellular matrix and mitochondrial alterations, as key molecular features of cachexia in non-small cell lung cancer. These clinically anchored proteomic and phosphoproteomic signatures provide potential targets for future research. Competing Interest Statement Seppo W. Langer: Research collaboration, speaker fee and advisory board honorarium: Amgen, Roche, Pfizer, Johnson and Johnson, Bristol Myers Squibb, Ipsen, Boehringer Ingelheim, Daiichi Dankyo.