Genetics of ABCB1 in Cancer

Skinner, Katie T.; Palkar, Antara M.; Hong, Andrew L.

doi:10.3390/cancers15174236

Cited by 25 publications

(3 citation statements)

References 120 publications

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“…Despite the cross-resistance, we did not observe any overrepresented genes with missense mutations or shared CNVs that were found in the ETP, PTX and DOX lines but not GEM (Table S7 ). Because automated analysis of WES could miss smaller CNVs and because ABCB1 has been linked to both ETP, DOX and PTX resistance 60 but not GEM, we examined the ABCB1 region manually using IGV. These data showed a large increase in read coverage for EPT-R1 and EPT-R2 relative to WT-3 parent line (Fig.…”

Section: Resultsmentioning

confidence: 99%

In vitro evolution and whole genome analysis to study chemotherapy drug resistance in haploid human cells

Jado,

Dow,

Carolino

et al. 2024

Sci Rep

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In vitro evolution and whole genome analysis has proven to be a powerful method for studying the mechanism of action of small molecules in many haploid microbes but has generally not been applied to human cell lines in part because their diploid state complicates the identification of variants that confer drug resistance. To determine if haploid human cells could be used in MOA studies, we evolved resistance to five different anticancer drugs (doxorubicin, gemcitabine, etoposide, topotecan, and paclitaxel) using a near-haploid cell line (HAP1) and then analyzed the genomes of the drug resistant clones, developing a bioinformatic pipeline that involved filtering for high frequency alleles predicted to change protein sequence, or alleles which appeared in the same gene for multiple independent selections with the same compound. Applying the filter to sequences from 28 drug resistant clones identified a set of 21 genes which was strongly enriched for known resistance genes or known drug targets (TOP1, TOP2A, DCK, WDR33, SLCO3A1). In addition, some lines carried structural variants that encompassed additional known resistance genes (ABCB1, WWOX and RRM1). Gene expression knockdown and knockout experiments of 10 validation targets showed a high degree of specificity and accuracy in our calls and demonstrates that the same drug resistance mechanisms found in diverse clinical samples can be evolved, discovered and studied in an isogenic background.

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Section: Resultsmentioning

confidence: 99%

In vitro evolution and whole genome analysis to study chemotherapy drug resistance in haploid human cells

Jado,

Dow,

Carolino

et al. 2024

Sci Rep

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“…In cancers, an elevated copy number of a gene itself cannot inherently enhance cell growth or survival unless subjected to additional selection pressure, such as for the ABCB1 oncogene included in this study. The protein coded for by this gene is recognized for its involvement in conferring resistance to chemotherapeutic drugs in cancer cells and requires a substantial amount of energy to function (41). Therefore, cells are not inclined to maintain a high level of this protein unless under certain selection pressure.…”

Section: Drug Selection Induces Retention Of Crispr-c Targeted Multi-...mentioning

confidence: 99%

Generative Modelling of Oncogene-carrying Extrachromosomal Circular DNA Biogenesis and Dynamics in Cells

Haskó,

Feng,

Arshadi

et al. 2024

Preprint

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Extrachromosomal circular DNAs (ecDNA) are focal gene amplifications frequently associated with cancer development and often indicating a poor prognosis. To understand the early dynamics of oncogene-carrying ecDNAs, we previously developed CRISPR-C, a tool for precise ecDNA generation by deleting specific chromosomal regions. Here, we adapted CRISPR-C to recreate tumor ecDNAs. This method also allowed us to enhance ecDNA generation efficiency by directly delivering Cas9 protein and sgRNAs as a ribonucleoprotein complex. By using the modified CRISPR-C, we successfully generated ecDNAs carrying oncogenes (EGFR, CDK4, MDM2, MYC, MYCN, FGFR2, ABCB1, and DHFR) in various human cell types. Furthermore, we demonstrated that our method could generate chimeric ecDNAs composed of target sequences from distant intra or inter-chromosomal regions. Using these generative ecDNA cell models, we studied the oncogene ecDNA expression and stability. The MDM2 expression was increased after CRISPR-C, while CDK4 was decreased indicating genomic-context dependent effect. The copy number of CRISPR-C generated CDK4 was ecDNA increased in cells after a long period of treatment with the CDK4 inhibitor palbociclib. Unlike CDK4, the CRISPR-C generated ABCB1 ecDNA was unstable in cells under normal growth conditions, but is stably retained when the cells were treated with colcemid, a recognized substrate for ABCB1. We thus provide valuable tools and an attractive platform for studying ecDNA biogenesisy and in vitro drug screening on ecDNA stability.

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“…ABCB1 is highly polymorphic in nature, where 1236C>T, 2677G>T/A, and 3435C>T are the most commonly studied polymorphisms for their association with drug pharmacokinetics and chemotherapy dependent toxicity reactions [8,[10][11][12]. Several studies deduced the effective contribution of ABCB1 gene polymorphisms in increased risk of cancer, treatment response and chemotherapy induced toxicity in different cancer patients [9,[13][14][15][16][17][18][19][20]. However, very limited information is available on polymorphisms of ABCB1 gene and their role in either paclitaxel or Adriamycin related chemotherapy toxicities in breast or other cancers.…”

Section: Introductionmentioning

confidence: 99%

Influence of (C1236T and C3435T) Polymorphisms of ABCB1 Gene on Chemotherapy Treatment Outcome and Toxicity in Breast Cancer Patients

Gudur,

Bhosale,

Gudur

et al. 2024

Asian Pac J Cancer Prev

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Background: ATP Binding Cassette Transporters (ABCB1) gene plays an important role in transport of different metabolites and anticancer drugs across the cell membrane. There is lack of knowledge on ABCB1 gene polymorphism and its correlation with Adriamycin or paclitaxel based chemotherapy induced toxicity in breast cancer patients. Therefore in this study, we explored the correlation of ABCB1 polymorphisms gene on response and toxicity in adriamycin and paclitaxel based chemotherapy in breast cancer patients from Indian population. Methods: Two hundred BC patients receiving Adriamycin and paclitaxel chemotherapy were enrolled in this study and chemotherapy induced hematological and non-hematological toxicity reactions were noted. The polymorphisms in ABCB1 gene (C1236T, C3435T) were studied by PCR and RFLP analysis. Results: The univariate logistic regression analysis showed statistically significant negative association with protective effects of ABCB1 (C3435T) polymorphism with heterozygous genotype (OR=0.34, 95% CI: 0.13-0.89; p=0.027), homozygous variant genotype (OR=0.31, 95% CI: 0.10-0.99; p=0.049) and combined C/T+T/T genotypes (OR=0.33, 95% CI: 0.13-0.79; p=0.013) in relation with severe toxicity of chemotherapy induced nausea and vomiting in breast cancer patients treated with Adriamycin chemotherapy. The 3435 C>T polymorphism of ABCB1 gene with heterozygous C/T genotype showed significantly negative association (OR=0.37, 95% CI: 0.14-0.96; p=0.042) with peripheral neuropathy in patients treated primarily with paclitaxel thereafter Adriamycin. Conclusion:The findings obtained from this study revealed significant association of ABCB1 3435 C>T polymorphisms with nonhematological toxicity in response to adriamycin and paclitaxel based chemotherapy.

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Genetics of ABCB1 in Cancer

Cited by 25 publications

References 120 publications

In vitro evolution and whole genome analysis to study chemotherapy drug resistance in haploid human cells

In vitro evolution and whole genome analysis to study chemotherapy drug resistance in haploid human cells

Generative Modelling of Oncogene-carrying Extrachromosomal Circular DNA Biogenesis and Dynamics in Cells

Influence of (C1236T and C3435T) Polymorphisms of ABCB1 Gene on Chemotherapy Treatment Outcome and Toxicity in Breast Cancer Patients

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