Effects of ABCB1 and ABCG2 polymorphisms on the pharmacokinetics of abemaciclib

Aim: The adverse events of the CKD4/6 inhibitor abemaciclib are known to be dose dependent. However, its pharmacokinetics vary among individuals. Abemaciclib is reported to be transported by P-glycoprotein (P-gp) and the breast cancer resistance protein (BCRP). Therefore, we evaluated whether ABCB1 and ABCG2 gene polymorphisms could be pharmacokinetic predictive factors of abemaciclib. Methods: A total of 45 patients with breast cancer able to take abemaciclib (150 mg twice daily) for 2 weeks were evaluated to determine the association among abemaciclib concentrations, adverse events, and ABCB1 1236T>C, 2677G>T/A, 3435C>T, and ABCG2 421C>A gene polymorphisms. Results: The trough concentrations of abemaciclib were higher in the group with grade 2 or greater neutropenia, anemia, and thrombocytopenia as compared with the group with grades 0 or 1. No significant association was observed between ABCB1 1236T>C, 3435C>T, and ABCG2 421C>A gene polymorphisms and abemaciclib concentrations. However, in ABCB1 2677G>T/A polymorphisms, the concentrations of abemaciclib tended to be higher in the homozygous group (AA + AT) as compared with that in the wild-type and heterozygous group (GG + GA + GT) [222.8 (80.5–295.8) ng/mL vs. 115.8 (23.6–355.2) ng/mL, P = 0.11]. Hence, the ABCB1 2677G>T/A homozygous group had a significantly higher incidence of abemaciclib withdrawal and dose reduction within 4 weeks as compared than the wild-type and heterozygous group (67% vs. 33%, P = 0.03). Conclusions: The gene polymorphism of ABCB1 2677G> T/A might be a predictor of the pharmacokinetics and tolerability of abemaciclib.

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Faculty Opinions recommendation of Brain accumulation of the EML4-ALK inhibitor ceritinib is restricted by P-glycoprotein (P-GP/ABCB1) and breast cancer resistance protein (BCRP/ABCG2).

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725783242.793517907 ◽

2016 ◽

Author(s):

Susan Bates

Keyword(s):

Breast Cancer ◽

Breast Cancer Resistance Protein ◽

Cancer Resistance ◽

Glycoprotein P ◽

Alk Inhibitor ◽

P Glycoprotein ◽

Resistance Protein

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P-Glycoprotein and Breast Cancer Resistance Protein Restrict Apical-to-Basolateral Permeability of Human Brain Endothelium to Amyloid-β

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2009.42 ◽

2009 ◽

Vol 29 (6) ◽

pp. 1079-1083 ◽

Cited By ~ 73

Author(s):

Leon M Tai ◽

A Jane Loughlin ◽

David K Male ◽

Ignacio A Romero

Keyword(s):

Breast Cancer ◽

Human Brain ◽

Breast Cancer Resistance Protein ◽

Amyloid Β ◽

Cancer Resistance ◽

Glycoprotein P ◽

P Glycoprotein ◽

Resistance Protein ◽

The Brain

The clearance of amyloid beta (Aβ) from the brain represents a novel therapeutic target for Alzheimer's disease. Conflicting data exist regarding the contribution of adenosine triphosphatebinding cassette transporters to the clearance of Aβ through the blood-brain barrier. Therefore, we investigated whether Aβ could be a substrate for P-glycoprotein (P-gp) and/or for breast cancer resistance protein (BCRP) using a human brain endothelial cell line, hCMEC/D3. Inhibition of P-gp and BCRP increased apical-to-basolateral, but not basolateral-to-apical, permeability of hCMEC/D3 cells to 125l Aβ 1–40. Our in vitro data suggest that P-gp and BCRP might act to prevent the blood-borne Aβ 1–40 from entering the brain.

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Tetrahydrocannabinol and Its Major Metabolites are Not (or are poor) Substrates and Inhibitors of Human P‐glycoprotein (P‐gp/MDR1/ABCB1) and Breast Cancer Resistance Protein (BCRP/ABCG2)

The FASEB Journal ◽

10.1096/fasebj.2021.35.s1.01701 ◽

2021 ◽

Vol 35 (S1) ◽

Author(s):

Xin Chen ◽

Jashvant Unadkat ◽

Qingcheng Mao

Keyword(s):

Breast Cancer ◽

Breast Cancer Resistance Protein ◽

Cancer Resistance ◽

Glycoprotein P ◽

P Glycoprotein ◽

Resistance Protein

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Polymorphisms of T- cell leukemia 1A gene loci are not related to the development of adjuvant letrozole-induced adverse events in breast cancer

PLoS ONE ◽

10.1371/journal.pone.0247989 ◽

2021 ◽

Vol 16 (3) ◽

pp. e0247989

Author(s):

Gurusamy Umamaheswaran ◽

Dharanipragada Kadambari ◽

Suresh Kumar Muthuvel ◽

Naveena A. N. Kumar ◽

Biswajit Dubashi ◽

...

Keyword(s):

Breast Cancer ◽

Adverse Events ◽

Cancer Patients ◽

Genetic Association ◽

Gene Polymorphisms ◽

Current Evidence ◽

Study Cohort ◽

Breast Cancer Patients ◽

South Indian ◽

Significant Difference

Letrozole, an aromatase inhibitor (AI), is the first-line adjuvant drug for treating hormone receptor-positive (HR+) breast cancer in postmenopausal women. However, harmful adverse events (AEs) and significant differences in drug response among individuals remain a significant problem in clinical application. Current evidence suggests that the observed individual variation in the treatment outcomes of AI is conferred by genetic variants. Hence, in this study, we examined the association of TCL1A gene polymorphisms with letrozole-induced AEs. The study subjects were postmenopausal HR+ breast cancer patients who were receiving adjuvant letrozole. Genomic DNA was isolated by a routine standard phenol-chloroform method. In total, 198 South Indian patients were genotyped for four single nucleotide polymorphisms (SNPs) in the TCL1A gene loci by the TaqMan allelic discrimination assay using the RT-PCR system. We used the odds ratio and 95% confidence interval to assess the genetic association. Musculoskeletal (MS) AEs and vasomotor symptoms (VMSs) are the most common side effects observed in the study cohort. Among 198 patients, 81 experienced musculoskeletal toxicity, reporting MS-AEs, 57 had VMSs, and 33 of them had both. The most frequently identified polymorphic variants in the patient series were rs11849538 (G), with an allele frequency of about 27.3%, followed by rs7158782-G (27.3%), rs7159713-G (25.8%), and rs2369049-G (22.5%). The genetic association analysis indicated no significant difference in the proportion of TCL1A gene variants between patients with and without AEs on either MS-AEs or VMSs. Though we observed high LD in all patient groups, the inferred haplotypes displayed a non-significant association with letrozole-induced specific AEs. However, the SNP functionality analysis by RegulomeDB provided a 2b rank score for rs7158782, suggesting a potential biological function. Our findings suggest that TCL1A gene polymorphisms may not play any role in the prediction of letrozole-induced AEs in South Indian HR+ breast cancer patients.

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Genomic Instability and TP53 Genomic Alterations Associate With Poor Antiproliferative Response and Intrinsic Resistance to Aromatase Inhibitor Treatment

JCO Precision Oncology ◽

10.1200/po.18.00286 ◽

2019 ◽

pp. 1-11

Author(s):

Eugene F. Schuster ◽

Pascal Gellert ◽

Corrinne V. Segal ◽

Elena López-Knowles ◽

Richard Buus ◽

...

Keyword(s):

Breast Cancer ◽

Aromatase Inhibitor ◽

Genomic Instability ◽

Loss Of Heterozygosity ◽

Cancer Resistance ◽

Wild Type ◽

Intrinsic Resistance ◽

Ki 67 ◽

Primary Tumors ◽

Resistance To Treatment

PURPOSE Although aromatase inhibitor (AI) treatment is effective in estrogen receptor–positive postmenopausal breast cancer, resistance is common and incompletely explained. Genomic instability, as measured by somatic copy number alterations (SCNAs), is important in breast cancer development and prognosis. SCNAs to specific genes may drive intrinsic resistance, or high genomic instability may drive tumor heterogeneity, which allows differential response across tumors and surviving cells to evolve resistance to treatment rapidly. We therefore evaluated the relationship between SCNAs and intrinsic resistance to treatment as measured by a poor antiproliferative response. PATIENTS AND METHODS SCNAs were determined by single nucleotide polymorphism array in baseline and surgery core-cuts from 73 postmenopausal patients randomly assigned to receive 2 weeks of preoperative AI or no AI in the Perioperative Endocrine Therapy—Individualizing Care (POETIC) trial. Fifty-six samples from the AI group included 28 poor responders (PrRs, less than 60% reduction in protein encoded by the MKI67 gene [Ki-67]) and 28 good responders (GdRs, greater than 75% reduction in Ki-67). Exome sequencing was available for 72 pairs of samples. RESULTS Genomic instability correlated with Ki-67 expression at both baseline ( P < .001) and surgery ( P < .001) and was higher in PrRs ( P = .048). The SCNA with the largest difference between GdRs and PrRs was loss of heterozygosity observed at 17p (false discovery rate, 0.08), which includes TP53. Nine of 28 PrRs had loss of wild-type TP53 as a result of mutations and loss of heterozygosity compared with three of 28 GdRs. In PrRs, somatic alterations of TP53 were associated with higher genomic instability, higher baseline Ki-67, and greater resistance to AI treatment compared with wild-type TP53. CONCLUSION We observed that primary tumors with high genomic instability have an intrinsic resistance to AI treatment and do not require additional evolution to develop resistance to estrogen deprivation therapy.

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Multidrug Resistance Modulation Activity of Silybin Derivatives and Their Anti-Inflammatory Potential

Antioxidants ◽

10.3390/antiox9050455 ◽

2020 ◽

Vol 9 (5) ◽

pp. 455 ◽

Cited By ~ 4

Author(s):

Simona Dobiasová ◽

Kateřina Řehořová ◽

Denisa Kučerová ◽

David Biedermann ◽

Kristýna Káňová ◽

...

Keyword(s):

Multidrug Resistance ◽

Biological Activities ◽

Biologically Active ◽

Cancer Drug ◽

Optical Isomers ◽

Dependent Manner ◽

Cancer Resistance ◽

Glycoprotein P ◽

P Glycoprotein ◽

Dose Dependent

Silybin is considered to be the main biologically active component of silymarin. Its oxidized derivative 2,3-dehydrosilybin typically occurs in silymarin in small, but non-negligible amounts (up to 3%). Here, we investigated in detail complex biological activities of silybin and 2,3-dehydrosilybin optical isomers. Antioxidant activities of pure stereomers A and B of silybin and 2,3-dehydrosilybin, as well as their racemic mixtures, were investigated by using oxygen radical absorption capacity (ORAC) and cellular antioxidant activity (CAA) assay. All substances efficiently reduced nitric oxide production and cytokines (TNF-α, IL-6) release in a dose-dependent manner. Multidrug resistance (MDR) modulating potential was evaluated as inhibition of P-glycoprotein (P-gp) ATPase activity and regulation of ATP-binding cassette (ABC) protein expression. All the tested compounds showed strong dose-dependent inhibition of P-gp pump. Moreover, 2,3-dehydrosilybin A (30 µM) displayed the strongest sensitization of doxorubicin-resistant ovarian carcinoma. Despite these significant effects, silybin B was the only compound acting directly upon P-gp in vitro and also downregulating the expression of respective MDR genes. This compound altered the expression of P-glycoprotein (P-gp, ABCB1), multidrug resistance-associated protein 1 (MRP1, ABCC1) and breast cancer resistance protein (BCRP, ABCG2). 2,3-Dehydrosilybin AB exhibited the most effective inhibition of acetylcholinesterase activity. We can clearly postulate that silybin derivatives could serve well as modulators of a cancer drug-resistant phenotype.

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Breast Cancer Resistance Protein and Multidrug Resistance Protein 2 Mediate the Disposition of Leonurine-10-O-β-glucuronide

Current Drug Metabolism ◽

10.2174/1389200221999201116142742 ◽

2020 ◽

Vol 21 (13) ◽

pp. 1060-1067

Author(s):

Xiaocui Li ◽

Yushan Xie ◽

Wei Qu ◽

Xiaojun Ou ◽

Xiaowen Ou ◽

...

Keyword(s):

Breast Cancer ◽

Multidrug Resistance ◽

Breast Cancer Resistance Protein ◽

Gene Knockout ◽

Multidrug Resistance Protein ◽

Cancer Resistance ◽

Wild Type ◽

Multidrug Resistance Protein 2 ◽

Intestinal Microsomes ◽

Resistance Protein

Background: Leonurine (Leo), a promising antilipemic agent that has been approved for clinical trials, is extensively metabolized into bioactive Leonurine-10-O-β-glucuronide (L-10-G) vivo. Objective: To explore the effects of breast cancer resistance protein (Bcrp) and multidrug resistance protein 2 (Mrp2) on the disposition of L-10-G. Methods: The pharmacokinetics, tissue distribution and intestinal perfusion of Leo were studied by using efflux transporter gene knockout mouse models. The enzyme kinetics via liver and intestinal microsomes were also examined. Results: After intravenous injection with Leo, the AUC0-∞ values of L-10-G in Bcrp1-/- and Mrp2-/- mice were 1.55-fold and 16.80-fold higher, respectively, than those in wild-type FVB mice (P < 0.05). After oral administration, the AUC0-∞ value of L-10-G showed a 2.82-fold increase in Mrp2-/- mice compared with wild-type FVB mice (P < 0.05). After gavage with Leo for 10 and 25 min, the bile accumulation of L-10-G in Mrp2-/- mice was 3-fold and 22-fold lower, respectively, than that in wild-type FVB mice (P < 0.05). Besides, the intestinal excreted amount of L-10-G showed 2.22-fold and 2.68-fold decrease in Bcrp1-/- and Mrp2-/- mice, respectively, compared with that in wild-type FVB mice (P < 0.05). The clearance of L-10-G decreased in liver microsomes and increased in intestinal microsomes of Bcrp1-/- and Mrp2-/- mice compared to the wild-type FVB mice (P < 0.05). Conclusion: Both Bcrp and Mrp2 are involved in the disposition of L-10-G, and Mrp2 exhibits a superior influence.

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