ABCMdb

PMID: 22894673

Galvani E, Peters GJ, Giovannetti E
EGF receptor-targeted therapy in non-small-cell lung cancer: role of germline polymorphisms in outcome and toxicity.
Future Oncol. 2012 Aug;8(8):1015-29. doi: 10.2217/fon.12.89., [PubMed]

Sentences

No. Mutations Sentence Comment

35 ABCG2 p.Gln141Lys Polymorphism Location Proposed functional effect EGFR CA repeat Chrom. 7, intron 1 EGFR gene transcription declines with increasing number of CA repeats EGFR R497KA/G Chrom. 7, exon 13 Substitution of arginine by lysine is associated with decreased EGFR activity EGFR -216G/T Chrom. 7, promoter T allele is associated with higher EGFR promoter activity EGFR -191C/A Chrom. 7, exon 1 A allele is associated with increased EGFR protein production AKT1-SNP4 Chrom. 14, exon 11 A allele is associated with reduced AKT1 mRNA ABCG2 421C/A (Q141K) Chrom. 4, exon 5 A allele associated with reduced transport of TKIs ABCG2 -15622C/T Chrom. 4, promoter T allele is associated with lower ABCG2 expression ABCG2 1143C/T Chrom. 4, exon 4 T allele is associated with lower ABCG2 expression CYP3A5*3 Chrom. 7, exon 7 CYP3A5*3 variant is associated with significant reduction in CYP3A5 protein expression and activity CYP3A4*1B Chrom. 7, exon 7 CYP3A4*1B variant is associated with twofold higher promoter activity Chrom.: Chromosome; TKI: Tyrosine kinase inhibitor. Login to comment 57 ABCG2 p.Gln141Lys Study Patients (n) Studied polymorphisms Effects Ref. Cusatis et al. (2006) 124 ABCG2: 421C>A (Q141K) Heterozygosis is associated with diarrhea [67] Brugger et al. (2011) 889 EGFR: Intr1, mut, copy-num, expression; KRAS: mut EGFR mut are associated with longer PFS KRAS mut are associated with reduced PFS [70] Hamada et al. (2012) 50 ABCB1: 1236TT, 2677TT, 3435TT 1236TT, 2677TT and 3435TT are associated with higher plasma concentration and risk of developing toxicity [73] copy-num: Gene copy-number; DCR: Disease control rate; Intr1: Intron 1; mut: Mutations; OS: Overall survival; PFS: Progression-free survival; PR: Partial response; RR: Response rate; SD: Stable disease; SNP: Single nucleotide polymorphism; TTP: Time to progression. Login to comment 68 ABCG2 p.Gln141Lys In agreement with the previous study, EGFR activating muta‑ tions were associated with sensitivity to gefit‑ inib and OS, and short CA-repeat status was also correlated with better response and longer EGFR EGFEGF EGF ATP ATP P P Cell growth, proliferation, invasion, angiogenesis, metastasis and inhibition of apoptosis ABCG2/ABCB1 RAS RAF MEK ERK PI3K Akt mTor AKT AKT1-SNP4: A allele associated with reduced AKT1 mRNA Cytoplasmic membrane Cytoplasm Drug target CA repeat: EGFR gene transcription declines with increasing number of CA repeats R497KA/G: the substitution of arginine by lysine is associated with decreased EGFR activity 216G/T: T allele associated with higher EGFR promoter activity 191C/A: A allele associated with increased EGFR protein production Drug transporters ABCG2 421C/A (Q141K): A allele is related to reduced TKI transport ABCG2 15622C/T and 1143C/T: T allele is related to lower ABCG2 expression ABCB1 2677G>T/A: associated with reduced TKI clearance ABCB1 1236TT, 2677TT and 3435TT: genotype related to higher plasma concentration and risk of developing higher toxicity CYP450 CYP3A5*3: variant associated with significant reduction in protein activity CYP3A4*1B: variant associated with twofold higher promoter activity CYP2D6*1, *2xn: variants associated with extensive drug metabolizers CYP2D6*3, *4, *5, *6, *9, *14 and *29: variants associated with poor drug metabolizers CYP1A1*2A: variant correlated with EGFR activating mutations and EGFR TKI response CYPs Erlotinib Gefitinib Nucleus Figure 1. Login to comment 116 ABCG2 p.Gln141Lys In particular, the ABCG2 421C/A polymorphism, resulting in a glutamine-to-lysine amino acid change at position 141 (Q141K), has been correlated with the downregulation of ABCG2 and with increase in accumulation of both gefitinib and erlotinib [53]. Login to comment