Multi omics approach to unravel the regorafenib resistant mechanism in colorectal cancer and to identify novel anti cancer agents

Abstract

Acquired Drug resistance significantly contributes to cancer recurrence and fatality. Kinases play a pivotal role in cell survival and proliferation and hence inhibition of the kinases is one of the therapeutic strategies used in cancer therapy. The emergence of resistance development to these inhibitors was reported. The mechanism of acquired drug resistance against these muti kinase inhibitors is still to be explored. In this context our laboratory has developed a resistant cell line model against regorafenib, an approved multi kinase inhibitor for advanced colorectal cancer. A multi omics approach has been employed to understand the mechanism of resistance development. A comparative proteome, Phospho-proteome, exome, and methylome profiling were performed with Drug sensitive HCT116 And Drug resistant HCT116 cells. Elevated levels of PI3K/AKT/mTOR, eIF2, Glucose metabolism, and HIF signalling were recorded from proteome data in our regorafenib-resistant HCT116 cells. Additionally, we identified a large set of genes related to tight junctions, ABC transporters, apoptotic and PI3K/AKT/mTOR pathways to be mutated in resistance HCT116 cells in an exome study. Differential methylation of RNA polymerase, apoptotic, TGF-and#946; and Ras family-related genes are seen in our methylome data. Our findings suggest that the PI3K/AKT/mTOR pathway plays a significant role in the acquisition of resistance in HCT116 cells. A promising approach in cancer treatment involves combining therapies to increase survival rates and fight against drug resistance. We investigated the efficacy of combining regorafenib with Rapamycin and Torin1 (mTOR inhibitors) to counter resistance in colorectal cancer cells. By evaluating cytotoxicity pathways, in vitro toxicity, and mode of cell death induction, we seek to resensitize regorafenib-resistant HCT116 cells, potentially offering new avenues for treating colorectal cancer patients with acquired resistance against kinase inhibitors. Chemotherapy is a common cancer treatment that faces challenges.