Modulation of Human PXR by Novel KRAS-G12C Inhibitors: Implications in Cancer Therapy
Type of DegreePhD Dissertation
General Veterinary Medicine
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The nuclear receptor human pregnane xenobiotic receptor (hPXR) is a transcription factor responsible for the regulation of key drug metabolism enzymes (DMEs) and drug efflux pumps (DEPs), including cytochrome p450 3A4 (CYP3A4) and multidrug resistance protein 1 (MDR1). hPXR is activated by a broad array of xenochemicals, including anticancer drugs. Activation of hPXR has been correlated with the occurrence of chemoresistance through upregulation of CYP3A4 and MDR1. CYP3A4 and MDR1 together contribute to the metabolism and disposition of more than 50% of clinically active drugs. Therefore, during multidrug chemotherapy, induction of hPXR-regulated CYP3A4 and MDR1 by one drug leads to increased drug metabolism and transport of co-administered drugs in the regimen that are also substrates of these DMEs and DEPs, affecting their therapeutic efficacy, leading to chemoresistance. Conversely, if a drug antagonizes hPXR, then that drug serves a huge potential in overcoming hPXR agonist-induced chemoresistance during multidrug chemotherapy. Recently, novel small molecule inhibitors of KRAS-G12C have been developed for the treatment of cancers harboring a KRAS-G12C mutation. However, it is unknown whether these KRAS-G12C inhibitors have the potential to modulate hPXR and either induce or suppress hPXR-mediated chemoresistance. Both the clinical KRAS-G12C inhibitor Sotorasib (SOT) (Chapter II) and pre-clinical KRAS-G12C inhibitor ARS-1620 (ARS) (Chapter III), activated hPXR at their pharmacologically relevant concentrations, and induced hPXR-mediated CYP3A4 and MDR1 gene expression. Notably, SOT and ARS decreased the sensitivity of the human colon cancer cells to the chemotherapeutics, suggesting that SOT and ARS can induce anti-cancer drug resistance by activating hPXR during combination chemotherapy. These results caution the use of SOT and ARS in conjunction with other chemotherapy drugs metabolized and transported via hPXR target genes. Another clinical KRAS-G12C inhibitor, Adagrasib (ADA) (Chapter IV), at its clinically relevant concentrations, suppressed hPXR agonist-induced CYP3A4 and MDR1 gene expression and chemoresistance. Thus, ADA could be a potential candidate to overcome hPXR agonist-induced chemoresistance during combination chemotherapy.