Investigating drug resistance in RAS-driven models of colon cancer

Abstract

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the world, accounting for more than 900,000 deaths in 2020. A disproportionate number of these deaths are due to KRAS-mutant CRCs, which account for ~40% of all CRC cases and are notoriously resistant to most therapies. Despite showing great promise in preclinical studies, targeted therapies have performed sub-optimally in clinical trials for KRAS mutant cancers. The mechanisms by which RAS pathway inhibitors have failed to reduce tumour progression remains poorly understood and presents a huge clinically unmet need. This research addresses the significant gap in effective treatments for KRAS-mutant CRC by delving into the mechanisms underlying drug resistance, using advanced CRC models. Several studies have reported that drug resistance is an emergent feature of genetically complex tumours. To capture tumour genome complexity, I used a diverse panel of CRC models reflecting multigenic and heterogeneous nature of tumours. Our patient-specific Drosophila avatars and transgenic mouse models are designed to explore how genome complexity impacts drug response. Our models comprise alterations in at least three primary pathways implicated in CRCs– APC, KRAS and TP53, providing a robust platform for studying the cellular and molecular dynamics driven by oncogenic Ras signalling. Key findings demonstrate that CRC tumour complexity significantly impacts the efficacy of RAS-pathway inhibitors, which have shown limited success clinically. By characterizing these models, this research has uncovered that different stages of tumour development exhibit varying dependencies on the MAPK pathway, offering insights into the failure of existing therapies. Additionally, the study identifies and validates the upregulation of the glucuronidation detoxification pathway as a novel resistance mechanism, showing that targeted combination therapies can enhance drug efficacy within tumours. This comprehensive study not only deepens the understanding of CRC pathogenesis and resistance mechanisms but also opens avenues for developing more effective targeted therapies