Drug therapeutic efficiency and development of unfavorable pharmacologic responses as well as the disease predisposition are caused first of all by patient’s genetic features. Genetic variations in genes encoding drug-metabolizing enzymes and transporter proteins are essential to understand the ethnic differences in disease occurrence, development, prognosis, therapeutic response and toxicity of drugs. For that reason, it is necessary to establish the normative frequency distribution of genotypes and alleles of these genes in a particular population. Data on frequency of pharmacogenetic polymorphisms in the of Belarus population are limited. The goal of our investigation was to analyze the frequency distribution of genotypes and alleles of genes encoding drug-metabolizing enzymes (CYP1А2, CYP2D6 – I phase; GSTs, NAT2 – II phase) and transporter protein MDR1 in the population of Belarus and comparisons with other ethnic populations. Our results indicate that clinically important genes are genetically highly variable and differ considerably between populations. Differences in allele frequencies across continents should be considered when designing clinical trials of new drugs continents should be considered when designing clinical trials of new drugs.

Background: MET belongs to the semaphorin superfamily of signaling proteins, containing three protein families (semaphorins, plexins, MET and RON) that have central roles in cell signaling. The MET receptor tyrosine kinase is involved in regulating cell growth/proliferation, survival, angiogenesis, cell scattering, cell motility and migration. Mutations in MET have been identified in various human cancers including lung cancer and papillary renal cell carcinomas. MET mutations occur within the extracellular seven-blade β-propeller fold sema domain (E168D, L229F, S325G, N375S), the juxtamembrane domain (R988C, T1010I), and the kinase domain (M1268T). We hypothesized that these mutations would have differential effects on the kinase inhibition. Methods: We modeled the various MET mutations from different functional domains of the receptor using Cos-7 transfection cell system to determine their effect on MET signaling and sensitivity to a selective MET kinase inhibitor SU11274. Sensitivity to SU11274 inhibition was assayed by phospho-immunoblotting using phospho-specific antibody against the major tyrosine kinase phosphorylation epitopes pY1234/1235 of the MET kinase in vitro. Results: First, we identified that mutations in the sema and juxtamembrane domain were activating as defined by ligand-independent constitutive receptor activation. SU11274 was capable of inhibiting ligand induced signaling through the wild-type MET as well as mutant MET receptors harboring mutations in the sema, juxtamembrane and tyrosine kinase domain. However, SU11274 inhibition of mutant MET was mutation-dependent, with the juxtamembrane domain mutations R988C and T1010I resulting in a receptor form that was less sensitive to SU11274. Mutations in the sema and kinase domain also resulted in varying sensitivity to inhibition by SU11274 inhibition. Interestingly, the kinase domain L1243R mutation in MET (homologous to the epidermal growth factor receptor L858R-EGFR sensitizing mutation in lung cancer) substantially sensitized the mutant MET receptor to SU11274 inhibition with complete p-MET inhibition at 0.5 μM compared to 5 μM as in wild type. On the other hand, the activating M1268T mutation in the kinase domain was less sensitive to SU11274 than the wild type receptor. Conclusion: Mutations in the sema and juxtamembrane domain of MET result in receptor activation. The small molecule inhibitor SU11274 is active against wild type and various mutated MET receptor. Further studies to characterize the signaling effects and the mechanism of sensitivity and resistance of MET mutations to specific inhibitors are crucial in the successful development of therapeutic MET inhibitors in personalized cancer therapy.

among groups were estimated by χ 2 test, bone metastasis-free survival was analyzed by Kaplan-Meier method. The prognostic impact of clinicopathologic parameters and biomarker expression was evaluated by Cox propotional hazards model. Results: BSP expression was associated with BM(P=0.027), OPN expression could not reach statistical significance(P=0.495). Survival analysis demonstrated that strong expression of BSP(P=0.036), N stage(P=0.000) and overall stage(P=0.001) were associated with time interval to BM. Multivariate analysis showed BSP expression(RR=1.7 79,P=0.012) and overall stage(RR=1.620,P=0.005) were independent prognostic factors for BM.Conclusions: BSP protein expression in the primary resected NSCLC is strongly associated with BM and could be used to identify high-risk patients, and further improve treatment of NSCLC. Correlation of OPN protein expression and bone metastasis need further investigation.