Impact of ABCG2 Polymorphisms on the Clinical Outcome and Toxicity of Gefitinib in Non-Small-Cell Lung Cancer Patients

Abstract

The ABCG2 -15622C/T polymorphism and ABCG2 (1143C/T, -15622C/T) haplotype resulted in a gefitinib-dependent, moderate-to-severe diarrhea suggesting that these pharmacogenetic markers should be considered to optimize NSCLC treatment.

Modelling of atorvastatin pharmacokinetics and the identification of the effect of a BCRP polymorphism in the Japanese population

“…In addition, this SNP has been associated with increased plasma exposure to erlotinib [41] and higher risk for the development of gefitinib [42] and sunitinib [43] induced toxicity/ adverse events. The fact that an association between the rs2622604 genotype and statin kinetics was identified in this work is of particular importance, as up to now most of the BCRP-related pharmacogenetic research in this class of drugs focuses on the effects of the c.421C>A polymorphism.…”

On the pharmacogenetics of non-small cell lung cancer treatment

“…However, diarrhea was also correlated with the ABCG2 421C/A variant: 44% of gefitinib-treated NSCLC patients heterozygous for ABCG2 421C/A presented this adverse effect [83]. Conversely, no correlation between gefitinib-induced toxicity and ABCG2 421C/A was found in a population of 94 Caucasian NSCLC patients, where moderate-severe diarrhea correlated with the ABCG2 15622C/T polymorphism and the ABCG2 (1143C/T, −15622C/T) haplotype [79].…”

“…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 reduction of ABCG2 protein expression and/or activity and with increase accumulation of both gefitinib and erlotinib [78]. However, no correlation between ABCG2 421C/A polymorphism and protein expression, as well as with outcome after gefitinib treatment, was observed in 50 NSCLC tissues [79]. Similarly, the SATURN trial, evaluating erlotinib in 242 advanced NSCLC patients, did not report significant correlation between response to erlotinib treatment and the ABCG2 421C/A SNPs, whereas the EGFR 216T/T genotype was related with the development of skin toxicity [53].…”

Interaction of innovative small molecule drugs used for cancer therapy with drug transporters

“…In contrast to the study by Thomas et al (2009), in this study the ABCG2 c.421C>A polymorphism was not associated with erlotinib disposition (Rudin et al, 2008). HEK293 cells (Shukla et al, 2009), K562 cells (Kawahara et al, 2010), LLC-PK1 cells (Hu et al, 2009) MRP2 (ABCC2) Docetaxel Saos2 cells (Hu et al, 2009) MRP4 (ABCC4) PMEA Saos2 cells (Hu et al, 2009) BCRP (ABCG2) Estrone-3-sulfate (Ki = 0.32 mM), Hoechst 33342, methotrexate, pheophorbide A, rhodamine 123 HEK293 cells (Dai et al, 2009;Shukla et al, 2009), K562 cells (Kawahara et al, 2010), Saos2 cells (Hu et al, 2009), S1-M1-80 cells (Dai et al, 2009) (Li et al, 2007) c.421C>A Increased drug accumulation (ratio of trough concentrations at steady state to day 1 trough concentration; malignant solid tumours) (Li et al, 2007) c.421C>A Increased risk of diarrhea (non-small-cell lung cancer) (Cusatis et al, 2006) c.421C>A No influence on risk of skin toxicity (non-small-cell lung cancer) (Cusatis et al, 2006) c.421C>A No effect on adverse side effects for example, diarrhea, interstitial pneumonia (non-small-cell lung cancer) (Akasaka et al, 2010) -15622TT Increased risk of diarrhea (non-small-cell lung cancer) (Lemos et al, 2011) haplotype TT (c.1143C>T, -15622C>T)…”

“…Increased risk of higher grade diarrhea (non-small-cell lung cancer) (Lemos et al, 2011) P-glycoprotein (ABCB1) c.3435C>T No influence on pharmacokinetics (Li et al, 2007) c. 3435C>T No influence on risk of diarrhea (non-small-cell lung cancer) (Cusatis et al, 2006) c.3435C>T No influence on risk of skin toxicity (non-small-cell lung cancer) (Cusatis et al, 2006) Imatinib OATP1A2 (SLCO1A2)…”