Genetic variation in the ATP binding cassette transporter ABCC10 is associated with neutropenia for docetaxel in Japanese lung cancer patients cohort.
Adult
Aged
Antineoplastic Agents
/ pharmacology
Carcinoma, Non-Small-Cell Lung
/ drug therapy
Cell Line, Tumor
Docetaxel
/ pharmacology
Drug Resistance, Neoplasm
/ genetics
Female
Humans
Japan
Lung Neoplasms
/ drug therapy
Male
Middle Aged
Multidrug Resistance-Associated Protein 2
Multidrug Resistance-Associated Proteins
/ genetics
Neutropenia
/ chemically induced
Polymorphism, Single Nucleotide
ABC transporter
Docetaxel
Neutropenia
Single nucleotide polymorphism
Journal
BMC cancer
ISSN: 1471-2407
Titre abrégé: BMC Cancer
Pays: England
ID NLM: 100967800
Informations de publication
Date de publication:
19 Mar 2019
19 Mar 2019
Historique:
received:
04
07
2018
accepted:
06
03
2019
entrez:
21
3
2019
pubmed:
21
3
2019
medline:
19
7
2019
Statut:
epublish
Résumé
Docetaxel is a widely used cytotoxic agent for treatments of various cancers. The ATP binding cassette (ABC) transporter / multidrug resistance protein (MRP) ABCC10/MRP7, involved in transporting taxanes, has been associated with resistance to these agents. Since genetic variation in drug transporters may affect clinical outcomes, we examined whether polymorphism of ABCC10 could affect clinical responses to docetaxel. Using 18 NSCLC cell lines and CRISPR-based genome-edited HeLa cells, we analyzed whether genetic variants of ABCC10 (rs2125739, rs9349256) affected cytotoxicity to docetaxel. Subsequently, we analyzed genetic variants [ABCC10 (rs2125739), ABCB1 (C1236T, C3435T, G2677 T/A), ABCC2 (rs12762549), and SLCO1B3 (rs11045585)] in 69 blood samples of NSCLC patients treated with docetaxel monotherapy. Clinical outcomes were evaluated between genotype groups. In the cell lines, only one genetic variant (rs2125739) was significantly associated with docetaxel cytotoxicity, and this was confirmed in the genome-edited cell line. In the 69 NSCLC patients, there were no significant differences related to rs2125739 genotype in terms of RR, PFS, or OS. However, this SNP was associated with grade 3/4 neutropenia (T/C group 60% vs. T/T group 87%; P = 0.028). Furthermore, no patient with a T/C genotype experienced febrile neutropenia. Our results indicate that genetic variation in the ABCC10 gene is associated with neutropenia for docetaxel treatment.
Sections du résumé
BACKGROUND
BACKGROUND
Docetaxel is a widely used cytotoxic agent for treatments of various cancers. The ATP binding cassette (ABC) transporter / multidrug resistance protein (MRP) ABCC10/MRP7, involved in transporting taxanes, has been associated with resistance to these agents. Since genetic variation in drug transporters may affect clinical outcomes, we examined whether polymorphism of ABCC10 could affect clinical responses to docetaxel.
METHODS
METHODS
Using 18 NSCLC cell lines and CRISPR-based genome-edited HeLa cells, we analyzed whether genetic variants of ABCC10 (rs2125739, rs9349256) affected cytotoxicity to docetaxel. Subsequently, we analyzed genetic variants [ABCC10 (rs2125739), ABCB1 (C1236T, C3435T, G2677 T/A), ABCC2 (rs12762549), and SLCO1B3 (rs11045585)] in 69 blood samples of NSCLC patients treated with docetaxel monotherapy. Clinical outcomes were evaluated between genotype groups.
RESULTS
RESULTS
In the cell lines, only one genetic variant (rs2125739) was significantly associated with docetaxel cytotoxicity, and this was confirmed in the genome-edited cell line. In the 69 NSCLC patients, there were no significant differences related to rs2125739 genotype in terms of RR, PFS, or OS. However, this SNP was associated with grade 3/4 neutropenia (T/C group 60% vs. T/T group 87%; P = 0.028). Furthermore, no patient with a T/C genotype experienced febrile neutropenia.
CONCLUSIONS
CONCLUSIONS
Our results indicate that genetic variation in the ABCC10 gene is associated with neutropenia for docetaxel treatment.
Identifiants
pubmed: 30890141
doi: 10.1186/s12885-019-5438-2
pii: 10.1186/s12885-019-5438-2
pmc: PMC6425580
doi:
Substances chimiques
ABCC10 protein, human
0
ABCC2 protein, human
0
Antineoplastic Agents
0
Multidrug Resistance-Associated Protein 2
0
Multidrug Resistance-Associated Proteins
0
Docetaxel
15H5577CQD
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
246Subventions
Organisme : Grant-in-Aid from Nagoya City University Foundation
ID : 2015. no.6
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