Colon Cancer Cells Evade Drug Action by Enhancing Drug Metabolism

Abstract

AbstractColorectal cancer (CRC) is the second most deadly cancer worldwide. One key reason is the failure of therapies that target RAS proteins, which represent approximately 40% of CRC cases. Despite the recent discovery of multiple alternative signalling pathways that contribute to resistance, durable therapies remain an unmet need. Here, we use liquid chromatography/ mass spectrometry (LC/MS) analyses onDrosophilaCRC tumour models to identify multiple metabolites in the glucuronidation pathway—a toxin clearance pathway—as upregulated in trametinib-resistantRAS/APC/P53(“RAP”) tumours compared to trametinib-sensitiveRASG12Vtumours. Elevating glucuronidation was sufficient to direct trametinib resistance inRASG12Vanimals while, conversely, inhibiting different steps along the glucuronidation pathway strongly reversedRAPresistance to trametinib. For example, blocking an initial HDAC1-mediated deacetylation step with the FDA-approved drug vorinostat strongly suppressed trametinib resistance inDrosophila RAPtumours. We provide functional evidence that pairing oncogenic RAS with hyperactive WNT activity strongly elevates PI3K/AKT/GLUT signalling, which in turn directs elevated glucose and subsequent glucuronidation. Finally, we show that this mechanism of trametinib resistance is conserved in anKRAS/APC/TP53mouse CRC tumour organoid model. Our observations demonstrate a key mechanism by which oncogenic RAS/WNT activity promotes increased drug clearance in CRC. The majority of targeted therapies are glucuronidated, and our results provide a specific path towards abrogating this resistance in clinical trials.s