Brain accumulation of osimertinib and its active metabolite AZ5104 is restricted by ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein)

Hoppe, Stéphanie van; Jamalpoor, Amer; Rood, Johannes J.M.; Wagenaar, Els; Sparidans, Rolf W.; Beijnen, Jos H.; Schinkel, Alfred H.

doi:10.1016/j.phrs.2019.104297

Cited by 31 publications

(34 citation statements)

References 52 publications

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“…Meanwhile, cell cycle gene alterations such as CDK6 CNV were presented at higher ratio compared to previous studies. Here ABCB1 gene mutation which has been demonstrated as one of the resistant mechanisms of Osimertinib was also identified at a ratio of 5% (41,42). These discrepancies in the detection of resistant mechanism could be due to the different panel using in each study as well as difference in the ethnic background of patients enrolled.…”

Section: Discussionmentioning

confidence: 96%

Dynamic cfDNA Analysis by NGS in EGFR T790M-Positive Advanced NSCLC Patients Failed to the First-Generation EGFR-TKIs

Wang

et al. 2021

Front. Oncol.

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PurposeCirculating cell-free DNA (cfDNA) level has been demonstrated to be associated with efficacy in first generation EGFR TKIs in non-small cell lung cancer (NSCLC). However, the role of dynamic cfDNA analysis using next-generation sequencing (NGS) in patients with subsequent third-generation EGFR TKIs remains unclear.MethodsFrom 2016 to 2019, 81 NSCLC patients with EGFR T790M mutation either in tissue or plasma who received third-generation EGFR TKIs treatment were enrolled. CfDNA were sequenced by NGS with a 425-gene panel. The association of clinical characteristics, pretreatment, dynamic cfDNA and T790M level with outcomes in patients treated with the third-generation TKIs were analyzed.ResultsIn univariate analysis, the median PFS of patients with undetectable cfDNA level during treatment was significantly longer than those with detectable cfDNA (16.97 vs. 6.10 months; HR 0.2109; P < 0.0001). The median PFS of patients with undetectable T790M level during treatment was significantly longer than those with detectable T790M (14.1 vs. 4.4 months; HR 0.2192; P < 0.001). Cox hazard proportion model showed that cfDNA clearance was an independent predictor for longer PFS (HR 0.3085; P < 0.001) and longer OS (HR 0.499; P = 0.034). The most common resistant mutations of the third-generation TKIs were EGFR C797S (24%). CDK6 CNV, GRIN2A, BRCA2, EGFR D761N, EGFR Q791H, EGFR V843I, and ERBB4 mutation genes may possibly be new resistant mechanisms.ConclusionsPatients with undetectable cfDNA during the third-generation EGFR TKI treatment have superior clinical outcomes, and dynamic cfDNA analysis by NGS is valuable to explore potential resistant mechanisms.

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Section: Discussionmentioning

confidence: 96%

Dynamic cfDNA Analysis by NGS in EGFR T790M-Positive Advanced NSCLC Patients Failed to the First-Generation EGFR-TKIs

Wang

et al. 2021

Front. Oncol.

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“…As a consequence, ABCG2 restricts the uptake of its transported substrates in the gut, thereby limiting their absorption, and mediating their distribution, hepatobiliary excretion and intestinal elimination [21,22]. Several in vivo studies demonstrated that ABCG2 also limits the foetal and brain penetration of its substrates [21,23]. This protein also contributes to drug-drug interactions, and therefore affects drug efficacy and drug adverse effects [24,25].…”

Section: Introductionmentioning

confidence: 99%

Abcg2 transporter affects plasma, milk and tissue levels of meloxicam

García-Lino

Blanco-Paniagua

Astorga-Simon

et al. 2020

Biochemical Pharmacology

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ATP-binding cassette (ABCG2) is an efflux transporter that extrudes xenotoxins from cells in liver, intestine, mammary gland, brain and other organs, affecting the pharmacokinetics, brain accumulation and secretion into milk of several compounds, including antitumoral, antimicrobial and anti-inflammatory drugs. The aim of this study was to investigate whether the widely used anti-inflammatory drug meloxicam is an Abcg2 sustrate, and how this transporter affects its systemic distribution. Using polarized ABCG2-transduced cell lines, we found that meloxicam is efficiently transported by murine Abcg2 and human ABCG2. After oral administration of meloxicam, the area under the plasma concentration-time curve in Abcg2-/mice was 2-fold higher than in wild type mice (146.06 ± 10.57 µg•h/ml versus 73.80 ± 10.00 µg•h/ml). Differences in meloxicam distribution were reported for several tissues, with a 20-fold higher concentration in the brain of Abcg2-/compared to wild-type mice. Meloxicam secretion into milk was also affected by the transporter, with a 2.5-fold higher milk-to-plasma ratio in wild-type compared with Abcg2-/lactating female mice (0.58 ± 0.08 versus 0.23 ± 0.06). We conclude that Abcg2 is an important determinant of the plasma and brain distribution of meloxicam and is clearly involved in its secretion into milk.

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“…Hydrogen bonds were also found between Gln990 of TMH 12 and Gln725 of TMH7 with the amide moiety on 7-indole position of branebrutinib (Figure 6). P-gp-Overexpressing Cells Are Not Resistant to Branebrutinib P-glycoprotein is known to mediate the transport of many TKIs (Eechoute et al, 2011;Tang et al, 2011Tang et al, , 2012Robey et al, 2018;van Hoppe et al, 2019) and confer resistance to some of these TKIs (Mahon et al, 2003(Mahon et al, , 2008Hiwase et al, 2008), including the BTK inhibitor ibrutinib (van Hoppe et al, 2018). To this end, we examined whether P-gp-overexpressing cells are less susceptible to branebrutinib treatment by determining the cytotoxicity of branebrutinib in multiple pairs of drugsensitive parental cell lines and respective P-gp-overexpressing FIGURE 5 | Branebrutinib stimulates the ATPase activity of P-glycoprotein (P-gp).…”

Section: Docking Analysis Of Branebrutinib Binding To the Drug-binding Pocket Of P-gpmentioning

confidence: 99%

Branebrutinib (BMS-986195), a Bruton’s Tyrosine Kinase Inhibitor, Resensitizes P-Glycoprotein-Overexpressing Multidrug-Resistant Cancer Cells to Chemotherapeutic Agents

Murakami

et al. 2021

Front. Cell Dev. Biol.

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The overexpression of P-glycoprotein (P-gp/ABCB1), an ATP-binding cassette (ABC) drug transporter, often contributes to the development of multidrug resistance (MDR) in cancer cells. P-gp mediates the ATP hydrolysis-dependent efflux of a wide range of chemotherapeutic agents out of cancer cells, thereby reducing the intracellular drug accumulation and decreasing the chemosensitivity of these multidrug-resistant cancer cells. Studies with tyrosine kinase inhibitors (TKIs) in P-gp-overexpressing cells have shown that certain TKIs could reverse MDR mediated by P-gp, while some TKIs are transported by P-gp. In the present work, we explored the prospect of repositioning branebrutinib (BMS-986195), a highly selective inhibitor of Bruton’s tyrosine kinase (BTK), to resensitize P-gp-overexpressing multidrug-resistant cancer cells to chemotherapeutic agents. Our results demonstrated that branebrutinib is capable of reversing P-gp-mediated MDR at sub-toxic concentrations, most likely by directly inhibiting the drug transport function of P-gp. Our findings were supported by the result of branebrutinib stimulating the ATPase activity of P-gp in a concentration-dependent manner and the in silico study of branebrutinib binding to the substrate-binding pocket of P-gp. In addition, we found that branebrutinib is equally cytotoxic to drug-sensitive parental cell lines and the respective P-gp-overexpressing multidrug-resistant variants, suggesting that it is unlikely that the overexpression of P-gp in cancer cells plays a significant role in reduced susceptibility or resistance to branebrutinib. In summary, we discovered an additional pharmacological action of branebrutinib against the activity of P-gp, which should be investigated further in future drug combination studies.

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Brain accumulation of osimertinib and its active metabolite AZ5104 is restricted by ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein)

Cited by 31 publications

References 52 publications

Dynamic cfDNA Analysis by NGS in EGFR T790M-Positive Advanced NSCLC Patients Failed to the First-Generation EGFR-TKIs

Dynamic cfDNA Analysis by NGS in EGFR T790M-Positive Advanced NSCLC Patients Failed to the First-Generation EGFR-TKIs

Abcg2 transporter affects plasma, milk and tissue levels of meloxicam

Branebrutinib (BMS-986195), a Bruton’s Tyrosine Kinase Inhibitor, Resensitizes P-Glycoprotein-Overexpressing Multidrug-Resistant Cancer Cells to Chemotherapeutic Agents

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