title: WEE1 kinase polymorphism as a predictive biomarker for efficacy of platinum-gemcitabine doublet chemotherapy in advanced non-small cell lung cancer patients.
abstract: DNA-damaging agents are commonly used for first-line chemotherapy of advanced non-small cell lung cancer (NSCLC). As a G2/M checkpoint kinase, Wee1 can phosphorylate CDC2-tyr15 and induce G2/M cell cycle arrest in response to DNA damage. The correlation of WEE1 polymorphisms to the efficacy of chemotherapy was tested in 663 advanced NSCLC patients. WEE1 rs3910384 genotype correlated to overall survival (OS) and progress-free survival (PFS) of NSCLC patients treated with platinum-based chemotherapy. Sub-group analysis revealed that rs3910384 was particularly associated with the efficacy of doublet chemotherapy combining two DNA-damaging agents, i.e. platinum and gemcitabine. NSCLC patients with the WEE1 rs3910384 G/G homozygote genotype showed 13.5 months extended OS, 3.2 months extended PFS, and a 274% relative increase in their 3-year survival rate (from 7.4% to 27.7%) compared to the A/A+A/G genotype after treatment with platinum-gemcitabine regimen. This finding was reproduced in the validation cohort. We utilized a luciferase reporter assay and Electrophoretic Mobility Shift Assay (EMSA) to demonstrate that rs3910384-linked WEE1 promoter haplotype can mediate allele-specific transcriptional binding and WEE1 expression in DNA damage response. In conclusion, the WEE1 rs3910384 G/G homozygote genotype can be used as a selective biomarker for NSCLC patients to indicate treatment with platinum and gemcitabine regimen.
authors.affiliation: Central Laboratory.
authors.forename: Di
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Pathology.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Wu
authors.affiliation: Central Laboratory.
authors.forename: Yuli
authors.initials: Y
authors.lastname: Jiao
authors.affiliation: Department of Pathology.
authors.forename: Likun
authors.initials: L
authors.lastname: Hou
authors.affiliation: Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, P.R. China.
authors.forename: Daru
authors.initials: D
authors.lastname: Lu
authors.affiliation: Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine.
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine.
authors.forename: Chang
authors.initials: C
authors.lastname: Chen
authors.affiliation: Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, P.R. China.
authors.forename: Ji
authors.initials: J
authors.lastname: Qian
authors.affiliation: Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine.
authors.forename: Ke
authors.initials: K
authors.lastname: Fei
authors.affiliation: Central Laboratory.
authors.forename: Bo
authors.initials: B
authors.lastname: Su
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics*; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D011110:Polymorphism, Genetic; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D000093542:Gemcitabine
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D009944:Organoplatinum Compounds; D003841:Deoxycytidine; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; D000093542:Gemcitabine