Signal Transduction and Targeted Therapy
Selection of effective genes that accurately predict chemotherapy response could improve cancer outcomes. We compare optimized gene signatures for cisplatin, carboplatin, and oxaliplatin response in the same cell lines, and respectively validate each with cancer patient data. Supervised support vector machine learning was used to derive gene sets whose expression was related to cell line GI50 values by backwards feature selection with cross-validation. Specific genes and functional pathways distinguishing sensitive from resistant cell lines are identified by contrasting signatures obtained at extreme vs. median GI50 thresholds. Ensembles of gene signatures at different thresholds are combined to reduce dependence on specific GI50 values for predicting drug response. The most accurate gene signatures for each platin are: cisplatin: BARD1, BCL2, BCL2L1, CDKN2C, FAAP24, FEN1, MAP3K1, MAPK13, MAPK3, NFKB1, NFKB2, SLC22A5, SLC31A2, TLR4, TWIST1; carboplatin: AKT1, EIF3K, ERCC1, GNGT1, GSR, MTHFR, NEDD4L, NLRP1, NRAS, RAF1, SGK1, TIGD1, TP53, VEGFB, VEGFC; oxaliplatin: BRAF, FCGR2A, IGF1, MSH2, NAGK, NFE2L2, NQO1, PANK3, SLC47A1, SLCO1B1, UGT1A1. TCGA bladder, ovarian and colorectal cancer patients were used to test cisplatin, carboplatin and oxaliplatin signatures (respectively), resulting in 71.0%, 60.2% and 54.5% accuracy in predicting disease recurrence and 59%, 61% and 72% accuracy in predicting remission. One cisplatin signature predicted 100% of recurrence in non-smoking bladder cancer patients (57% disease-free; N=19), and 79% recurrence in smokers (62% disease-free; N=35). This approach should be adaptable to other studies of chemotherapy response, independent of drug or cancer types.