B21-08 Cachexia Phenotype Leads to Upregulated Pro-Tumorigenic Pathways in Patients With Late-Stage Non-Small Cell Lung Cancer

Cachexia phenotype is associated with a worse prognosis in patients with non-small cell lung cancer, but the pathophysiological events contributing to this process are not clearly defined. In this study, we evaluated the lower airway transcriptome to identify genes and associated pathways present among patients with cachexia and lung cancer that may contribute to a pro-tumorigenic process. 93 NSCLC patients who were treated with immunotherapy were categorized in cachexia and no cachexia groups (defined as no-CACS, n = 27). The cachexia group was further divided into 3 groups: patients with a cachexia diagnosis that resolved with immunotherapy treatment (CACS-R, n = 25), patients whose cachexia diagnosis continues throughout treatment (CACS-C,n=25), and those whose cachexia started after immunotherapy initiation (CACS-S, n = 16) . Lower airway samples were collected from these patients and their RNA was isolated for host transcriptome sequencing. Demographic analysis showed patients with continued cachexia were more likely to die within two years of diagnosis. Host transcriptomic analyses identified for differences between groups of patients with different cachexia phenotypes. Differential enrichment analyses showed DEGs between groups and were further used for ingenuity pathway analysis. For all three different cachexia phenotypes, as compared with the no cachexia group, we identified upregulation of pro-tumorigenic pathways. In total, there were 13,379 DEGs in the CACS-R, CACS-C, and CACS-S, as compared with the no-CACS group (Fig 1A, B and C ). We then evaluated for key pathways found dysregulated based on Ingenuity Pathway Analyses (Fig 1D). Among those, we noted that cachexia (all three different group types) was associated with upregulation of chromatin reorganization, processing of intron capped mRNA, mitotic metaphase and anaphase, and ILK signaling. We found multiome lower airway transcriptomic changes among patients with cachexia. These changes could potentially be related to abnormal processing of intron capped mRNA and expression of chromatin reorganization which could result in tumor cells having an enhanced ability to manipulate its processes, leading to pro-tumorigenic qualities. Similarly, atypical mitotic protein expression, such as those involved in metaphase and anaphase, could amplify proliferation processes. Finally, an upregulation of ILK signaling is closely related to cancer progression as it is involved in several pro-tumorigenic processes. Thus, patients diagnosed with cachexia during their lung cancer treatment seem to have transcriptomic signatures that are consistent with pathways previously described as important for cancer progression.