title: Important role of CYP2J2 in protein kinase inhibitor degradation: a possible role in intratumor drug disposition and resistance.
abstract: We have investigated in vitro the metabolic capability of 3 extrahepatic cytochromes P-450, CYP1A1, 1B1 and 2J2, known to be over-expressed in various tumors, to biotransform 5 tyrosine kinase inhibitors (TKI): dasatinib, imatinib, nilotinib, sorafenib and sunitinib. Moreover, mRNA expression of CYP1A1, 1B1, 2J2 and 3A4 in 6 hepatocellular and 14 renal cell carcinoma tumor tissues and their surrounding healthy tissues, was determined. Our results show that CYP1A1, 1B1 and especially 2J2 can rapidly biotransform the studied TKIs with a metabolic efficiency similar to that of CYP3A4. The mRNA expression of CYP1A1, 1B1, 2J2 and 3A4 in tumor biopsies has shown i) the strong variability of CYP expression and ii) distinct outliers showing high expression levels (esp. CYP2J2) that are compatible with high intratumoral CYP activity and tumor-specific TKI degradation. CYP2J2 inhibition could be a novel clinical strategy to specifically increase the intratumoral rather than plasma TKI levels, improving TKI efficacy and extending the duration before relapse. Such an approach would be akin to beta-lactamase inhibition, a classical strategy to avoid antibiotic degradation and resistance.
authors.affiliation: Université Paris Descartes, INSERM UMR S-U775, Sorbonne Paris Cité, Paris, France; Hôpital Européen Georges Pompidou, Service de Biochimie, Unité Fonctionnelle de Pharmacogénétique et Oncologie Moléculaire, Paris, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Narjoz
authors.affiliation: Quantitative Mass Spectrometry Facility, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Amélie
authors.initials: A
authors.lastname: Favre
authors.affiliation: Quantitative Mass Spectrometry Facility, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Justin
authors.initials: J
authors.lastname: McMullen
authors.affiliation: Quantitative Mass Spectrometry Facility, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Philippe
authors.initials: P
authors.lastname: Kiehl
authors.affiliation: University Hospital Zürich, Oncology, Zürich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Montemurro
authors.affiliation: Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.affiliation: Université Paris Descartes, INSERM UMR S-U775, Sorbonne Paris Cité, Paris, France; Hôpital Européen Georges Pompidou, Service de Biochimie, Unité Fonctionnelle de Pharmacogénétique et Oncologie Moléculaire, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Beaune
authors.affiliation: Université Paris Descartes, INSERM UMR S-U775, Sorbonne Paris Cité, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: de Waziers
authors.affiliation: Quantitative Mass Spectrometry Facility, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Rochat
mesh_terms: D001549:Benzamides / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D065633:Cytochrome P-450 CYP1B1 / Q000235:genetics; D000090762:Cytochrome P-450 CYP2J2; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D000069439:Dasatinib; D056945:Hep G2 Cells; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics; D009536:Niacinamide / Q000031:analogs & derivatives / Q000378:metabolism; D010671:Phenylurea Compounds / Q000378:metabolism; D010879:Piperazines / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000378:metabolism*; D011743:Pyrimidines / Q000378:metabolism; D011758:Pyrroles / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077157:Sorafenib; D000077210:Sunitinib; D013844:Thiazoles / Q000378:metabolism
chemical_list: D001549:Benzamides; C000717350:CYP2J2 protein, human; D007211:Indoles; D010671:Phenylurea Compounds; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D013844:Thiazoles; D009536:Niacinamide; D000068877:Imatinib Mesylate; D003577:Cytochrome P-450 Enzyme System; D000077157:Sorafenib; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D000090762:Cytochrome P-450 CYP2J2; D051544:Cytochrome P-450 CYP3A; C498826:nilotinib; D000069439:Dasatinib; D000077210:Sunitinib