Table 4.
Pharmacogenomics of small molecules used for cancer therapy. The influence of drug uptake and efflux transporters on pharmacokinetics (PK) and/or pharmacodynamics (PD) are shown
| Drug | Transporter (gene) | Genotype/polymorphism | Effect on PK | Effect on PD (outcome, toxicity) | Reference |
|---|---|---|---|---|---|
| Erlotinib | BCRP (ABCG2) | c.421C>A | Clearance reduced by 24% (head and neck squamous cell carcinoma) | (Thomas et al., 2009) | |
| c.1143/−15622 diplotypes (CC/TT) or (TT/TT) | Higher AUC and Cmax (non-small-cell lung cancer, head and neck cancer, and ovarian cancer) | No influence on diarhea or skin toxicity | (Rudin et al., 2008) | ||
| P-glycoprotein (ABCB1) | c.2677G>T/A | No influence on pharmacokinetics (head and neck squamous cell carcinoma) | (Thomas et al., 2009) | ||
| c.3435C>T | No influence on pharmacokinetics (head and neck squamous cell carcinoma) | (Thomas et al., 2009) | |||
| Gefitinib | BCRP (ABCG2) | c.421C>A | Trend to higher Css, min (n.s., trough concentrations at steady state; malignant solid tumours) | (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) | −361GG | Reduced imatinib clearance (CML) | (Yamakawa et al., 2011) | |
| OATP1B3 (SLCO1B3) | c.334T>G | No influence on plasma trough concentrations (CML) | Higher rates of major molecular response (CML) | (Takahashi et al., 2010) | |
| c.334T>G | Higher intracellular concentrations of imatinib in leukocytes (chronic phase CML) | (Nambu et al., 2011) | |||
| c.334T>G | Higher intracellular (leukocytes) to plasma ratio of imatinib (chronic phase CML) | (Nambu et al., 2011) | |||
| OCT1 (SLC22A1) | c.156T>C | No influence on plasma trough concentrations (CML) | No influence on major molecular response (CML) | (Takahashi et al., 2010) | |
| c.286C>T | No change in oral imatinib clearance | (Hu et al., 2008) | |||
| c.480GG | Increased risk for imatinib resistance due to loss of response and treatment failure (CML) | (Kim et al., 2009) | |||
| c.480C>G | No influence on plasma trough concentrations (CML) | No influence on major molecular response (CML) | (Takahashi et al., 2010) | ||
| c.1022C>T | No influence on plasma trough concentrations (CML) | No influence on major molecular response (CML) | (Takahashi et al., 2010) | ||
| c.1222GG | No influence on plasma trough concentrations (CML) | Higher rates of major molecular response (CML) | (Takahashi et al., 2010) | ||
| c.1498C>A | No change in oral imatinib clearance | (Hu et al., 2008) | |||
| BCRP (ABCG2) | c.34GG | Decreased major and complete cytogenetic response (CML) | (Kim et al., 2009) | ||
| c.421CC | Decreased complete molecular response (CML) | (Kim et al., 2009) | |||
| c.421C>A | No influence on oral clearance (GIST) | (Gardner et al., 2006) | |||
| c.421C>A | Increased plasma trough concentrations (CML) | No influence on major molecular response (CML) | (Takahashi et al., 2010) | ||
| P-glycoprotein (ABCB1) | c.3435TT | Decreased overall survival (univariate analysis, CML) | (Kim et al., 2009) | ||
| c.3435C>T | No influence on the oral clearance (GIST) | (Gardner et al., 2006) | |||
| c.1236TT; c.2677TT; c.3435TT | Increased oral clearance (GIST) | (Gurney et al., 2007) | |||
| c.1236C>T | Higher major molecular response (CML) | (Dulucq et al., 2008) | |||
| c.1236C>T | Higher imatinib trough concentrations (CML) | (Dulucq et al., 2008) | |||
| c.1236TT | Increased resistance [cytogenetic resistance or relapse after major cytogenetic response (MCyR, CML)] | (Ni et al., 2011) | |||
| c.1236C>T | No influence on plasma trough concentrations (CML) | No influence on major molecular response (CML) | (Takahashi et al., 2010) | ||
| c.2677TT / TA | Higher major molecular response (CML) | (Dulucq et al., 2008) | |||
| c.2677GT | Increased resistance (cytogenetic resistance or relapse after MCyR) | (Ni et al., 2011) | |||
| c.2677G>T/A | No influence on plasma trough concentrations (CML) | No influence on major molecular response (CML) | (Takahashi et al., 2010) | ||
| c.2677AG / AT / AA | Lower resistance (cytogenetic resistance or relapse after MCyR) | (Ni et al., 2011) | |||
| c.3435CC | Lower resistance (cytogenetic resistance or relapse after MCyR) | (Ni et al., 2011) | |||
| c.3435C>T | No influence on plasma trough concentrations (CML) | No influence on major molecular response (CML) | (Takahashi et al., 2010) | ||
| haplotype TC or TT (c.1236C>T; c.3435C>T | Higher imatinib trough concentrations (CML) | (Dulucq et al., 2008) | |||
| c.1236C; c.2677G; c.3435C | Lower major molecular response (CML) | (Dulucq et al., 2008) | |||
| MRP2 (ABCC2) | −24C>T | No influence on plasma trough concentrations (CML) | No influence on major molecular response (CML) | (Takahashi et al., 2010) | |
| Sunitinib | BCRP (ABCG2) | c.34G>A | Trend for increased progression free survival (n.s., clear-cell metastatic renal cell carcinoma) | (van der Veldt et al., 2011) | |
| 422AA | Higher blood concentrations (renal cell carcinoma) | (Mizuno et al., 2010) | |||
| haplotype TT; −15622C>T, c.1143C>T | Increased risk for toxicity (>grade 2 CTCAE, metastatic renal cell carcinoma, GIST) | (van Erp et al., 2009a) | |||
| P-glycoprotein (ABCB1) | haplotype TCG (c.3435C>T; c.1236C>T; c.2677G>T) | Increased progression free survival (clear-cell metastatic renal cell carcinoma) | (van der Veldt et al., 2011) | ||
| haplotype TTT (c.1236C>T, c.2677G>T, c.3435C>T) | Increased risk for hand-foot syndrome (metastatic renal cell carcinoma, GIST) | (van Erp et al., 2009a) |
GIST, gastrointestinal stromal tumours.