COMPUTATIONAL DISCOVERY OF NOVEL THERAPEUTIC INTERFACES BETWEEN TRAIL RECEPTORS AND POTENTIAL DRUG TARGETS IN KIDNEY CANCER: A BIOINFORMATICS AND DRUG DISCOVERY STUDY

Abstract

Background: This study highlights the need for a new therapeutic targets, for an improved targeted therapies in kidney renal clear cell carcinoma (KIRC) due to limitations in effective treatment of  currently available KIRC therapeutic strategies. Aim: This investigation aims to identify novel therapeutic targets in kidney renal clear cell carcinoma (KIRC) by examining tumor associated genes that show strong correlations with circulating tumor markers and highly expressed inflammatory cytokines. Materials and Methods: Clinical and genomic data from 1848 patients with kidney renal clear cell carcinoma were obtained from The Cancer Genome Atlas and analyzed using cBioPortal, STRING, and STITCH, together with computational workflows implemented in Python and R, to identify potential therapeutic targets in renal cancer. Results: Our Bioinformatics analysis identified novel direct interactions between TRAIL and potential therapeutic targets including MAP3K1, MAP3K3, MAP2K4, PIK3CA, PIK3CB, PIK3R1, SMPD1, sphingomyelin, CHUK (IKKα), and IKBKG in KIRC. These findings highlight new molecular targets for therapeutic discovery and the improvement of TRAIL based treatment strategies. Network analysis further showed that TRAIL functions as a key regulatory gene interacting with 18 agonistic and antagonistic drug targets within KIRC signaling pathways. Our findings suggest that combining TRAIL with agonists such as TRADD, SMPD1, CASP8, CASP10, TNFRSF10A/B, FADD, MAPK8, ubiquitinated RIPK1, and ceramide, or pairing TRAIL with inhibitors targeting antagonists including TRAF2, MAPK3, MAPK1, IKBKB, TNFRSF10C, CFLAR, and deubiquitinated RIPK1, may disrupt key oncogenic pathways and improve therapeutic outcomes in KIRC. Conclusion: The novel TRAIL target direct associations identified in this study reveal previously unrecognized TRAIL interactions in KIRC. These findings provide new insight into molecular mechanisms that may influence therapeutic resistance and patient survival in KIRC and offer a stronger foundation for the development of improved targeted treatment strategies.