A Gene Expression Signature of Acquired Chemoresistance to Cisplatin and Fluorouracil Combination Chemotherapy in Gastric Cancer Patients

BackgroundWe initiated a prospective trial to identify transcriptional alterations associated with acquired chemotherapy resistance from pre- and post-biopsy samples from the same patient and uncover potential molecular pathways involved in treatment failure to help guide therapeutic alternatives. Methodology/Principal FindingsA prospective, high-throughput transcriptional profiling study was performed using endoscopic biopsy samples from 123 metastatic gastric cancer patients prior to cisplatin and fluorouracil (CF) combination chemotherapy. 22 patients who initially responded to CF were re-biopsied after they developed resistance to CF. An acquired chemotherapy resistance signature was identified by analyzing the gene expression profiles from the matched pre- and post-CF treated samples. The acquired resistance signature was able to segregate a separate cohort of 101 newly-diagnosed gastric cancer patients according to the time to progression after CF. Hierarchical clustering using a 633-gene acquired resistance signature (feature selection at PAKT1, EIF4B, and RPS6 (mTOR pathway), DNA repair and drug metabolism genes, and was enriched for genes overexpressed in embryonic stem cell signatures. A 72-gene acquired resistance signature (a subset of the 633 gene signature also identified in ES cell-related gene sets) was an independent predictor for time to progression (adjusted P = 0.011) and survival (adjusted P = 0.034) of these 101 patients. Conclusion/SignificanceThis signature may offer new insights into identifying new targets and therapies required to overcome the acquired resistance of gastric cancer to CF.

研究背景：本研究启动一项前瞻性试验，旨在从同一患者的化疗前及化疗后活检样本中，筛选与获得性化疗耐药相关的转录组改变，并揭示参与治疗失败的潜在分子通路，以期为治疗方案的选择提供指导。
研究方法与主要结果：本研究针对123例转移性胃癌患者，在接受顺铂（cisplatin）联合氟尿嘧啶（fluorouracil, CF）化疗前采集其内镜活检样本，开展前瞻性高通量转录组分析。其中22例初始对CF化疗应答的患者，在出现CF化疗耐药后再次接受活检。通过比对分析上述患者化疗前后配对样本的基因表达谱，我们筛选出获得性化疗耐药特征基因集。该耐药特征基因集可基于101例新确诊胃癌患者接受CF化疗后的进展时间进行群体分型。本研究采用包含633个基因的获得性耐药特征基因集进行层级聚类，该特征集的筛选基于PAKT1、EIF4B、RPS6（mTOR通路）、DNA修复及药物代谢相关基因，且其富集了在胚胎干细胞（Embryonic Stem Cell, ESC）特征中高表达的基因。进一步分析发现，其中72个基因构成的耐药特征基因集（为上述633基因集的子集，同时也在胚胎干细胞相关基因集内被鉴定到）可作为这101例患者化疗进展时间（校正P=0.011）及总生存期（校正P=0.034）的独立预测因子。
研究结论与意义：该耐药特征基因集可为筛选克服胃癌对CF化疗获得性耐药的新型治疗靶点与治疗方案提供新的研究思路。