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<p>Colorectal cancer (CRC) is the second leading cause of cancer deaths worldwide. One key reason is the lack of durable therapies that target KRAS-dependent disease, which represents approximately 40% of CRC cases. Here, we use liquid chromatography/mass spectrometry (LC/MS) analyses on <i>Drosophila</i> CRC tumour models to identify multiple metabolites in the glucuronidation pathway—a toxin clearance pathway that impacts most drugs—as upregulated in trametinib-resistant <i>RAS/APC/P53</i> (“<i>RAP</i>”) tumours compared to trametinib-sensitive <i>Ras</i><sup><i>G12V</i></sup> single mutant tumours. Genetic inhibition of different steps along the glucuronidation pathway strongly reversed <i>RAP</i> resistance to trametinib; conversely, elevating glucuronidation pathway activity was sufficient to direct trametinib resistance in <i>Ras</i><sup><i>G12V</i></sup> animals. Mechanistically, pairing oncogenic RAS with hyperactive WNT activity strongly elevated PI3K/AKT/GLUT signalling, which in turn directed elevated glucose uptake and glucuronidation; our data also implicate the pentose phosphate pathway in this process. We provide evidence that this mechanism of trametinib resistance is conserved in a <i>KRAS/APC/TP53</i> mouse CRC tumour organoid model. Finally, we identify two clinically accessible approaches to inhibiting drug glucuronidation: (i) blocking an initial HDAC1-mediated deacetylation step of trametinib with the FDA-approved drug vorinostat; (ii) reducing blood glucose by the alpha-glucosidase inhibitor acarbose. Overall, our observations demonstrate a key mechanism by which oncogenic RAS/WNT activity promotes increased drug clearance in CRC and provides a practical path towards abrogating drug resistance in CRC tumours.</p>

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Colon cancer cells evade drug action by enhancing drug metabolism

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月10日

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  • Bojie Cong,
  • Teena Thakur,
  • Alejandro Huerta Uribe,
  • Evangelia Stamou,
  • Sindhura Gopinath,
  • Owen Sansom,
  • Oliver Maddocks,
  • Ross Cagan

摘要

Colorectal cancer (CRC) is the second leading cause of cancer deaths worldwide. One key reason is the lack of durable therapies that target KRAS-dependent disease, which represents approximately 40% of CRC cases. Here, we use liquid chromatography/mass spectrometry (LC/MS) analyses on Drosophila CRC tumour models to identify multiple metabolites in the glucuronidation pathway—a toxin clearance pathway that impacts most drugs—as upregulated in trametinib-resistant RAS/APC/P53 (“RAP”) tumours compared to trametinib-sensitive RasG12V single mutant tumours. Genetic inhibition of different steps along the glucuronidation pathway strongly reversed RAP resistance to trametinib; conversely, elevating glucuronidation pathway activity was sufficient to direct trametinib resistance in RasG12V animals. Mechanistically, pairing oncogenic RAS with hyperactive WNT activity strongly elevated PI3K/AKT/GLUT signalling, which in turn directed elevated glucose uptake and glucuronidation; our data also implicate the pentose phosphate pathway in this process. We provide evidence that this mechanism of trametinib resistance is conserved in a KRAS/APC/TP53 mouse CRC tumour organoid model. Finally, we identify two clinically accessible approaches to inhibiting drug glucuronidation: (i) blocking an initial HDAC1-mediated deacetylation step of trametinib with the FDA-approved drug vorinostat; (ii) reducing blood glucose by the alpha-glucosidase inhibitor acarbose. Overall, our observations demonstrate a key mechanism by which oncogenic RAS/WNT activity promotes increased drug clearance in CRC and provides a practical path towards abrogating drug resistance in CRC tumours.