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1、肺癌耐药分子标志 与个体性化疗徐 萌暨南大学附属第一医院肿瘤科肺癌耐药分子标志：药理遗传学和药理基因 组学的研究表明与肺癌多药耐药相关的基因 及其异常信号传导通路。个体性化疗：根据肺癌患者药理遗传学和基 因组学特点，采用特异和最佳的化疗药物方 案，提高化疗疗效，尽量降低化疗副反应， 最大延长患者生存期。 1 肺癌化疗耐药的复杂性 2 肺癌耐药逆转药物的局限性3 肺癌个体性化疗的实践性4 典型病例l 以铂类药物为基础的联合化疗比单一化疗效果好，是 中晚期肺癌一线治疗的金标准;l 紫杉醇、诺维本、多西紫杉醇、吉西他滨;l 在过去三十年中，非小细胞肺癌的中位生存时间只延 长了大约三个月;l 中晚期非
2、小细胞肺癌经验性化疗疗效停滞于平台期， 致力于寻找各种敏感的化疗耐药分子标志和高效的耐 药逆转剂具有广泛的应用前景。Corey Langer 2000; Breathnach et al 2001; Schiller et al 2002 一. 肺癌化疗耐药的复杂性What is the Scope of the Problem?New Cancer Cases 121:823-835K-ras conditioning mouselimiting dilution assayStem Cells-Drug Resistancen High levels of ABC drug transpo
3、rtersn Quiescencen Capacity for DNA repairn Accumulation of mutationsNature Review Cancer 2005;5:275-284Nature Review Drug Discovery 2006;5:219-234Resistance-ABC TransporterTargeting ABC TransporterNature Review Drug Discovery 2006;5:219-234Cancer Stem Cell -high drug efflux capacitynCancer stem cel
4、l has ABC transporters with drug-efflux capacity.Proc. Natl. Acad. Sci. USA 101, 1422814233 (2004)human tumor cell linesSP: side populationJF N Engl J Med, 2002lPlatinum doublets have a marginally increased RR (17%) vs third generation non-platinum doublets but OS is not improved.DAddario, Pintilie
5、et al.; J Clin Oncol, 2005Clinically important mediators of DNA repair for platinum based damagel Essential NER DNA unwinding: ERCC2 (XPD) Incision of DNA: ERCC1 (XPF)l Transcription coupled NER BRCA1l Base Excision Repair XRCC1General mechanisms of platinum resistance l Detoxificationl Inhibitors o
6、f apoptosisl DNA methylationl Changes in influx/effluxl Increased DNA repair capacityRabik and Dolan; Cancer Treat Rev, 2006Established mediators of platinum resistance in NSCLCl BRCA1l ERCC1 Germline polymorphisms Tumor expression by mRNA Immunohistochemistryl Polymorphisms in ERCC2 Hum Mol Genet,
7、2004BRCA1 mRNA expression levels and survival in NSCLC patients treated with neo-adjuvant gemcitabine Bottom: N=15, Middle=28, Top=12; p=0.01 Taron, Rosell et al.; Hum Mol Genet, 2004Two strands of evidence for customizing therapy based on BRCA1 mRNA levels in SCATlAmong several DNA repair genes, BR
8、CA1 is the most reliable predictive marker of chemotherapy outcome in stage IV and stage III NSCLClIn early-stage chemonaive NSCLC patients, BRCA1 is the best prognostic marker of survivallBRCA1 has been selected as the marker for assigning chemotherapy in the SCAT experimental armLow BRCA1 gem/cisI
9、ntermediate BRCA1 doc/cisHigh BRCA1 docResected NSCLC pN1 / pN2Q 2 ASCO 07Increased BRCA1 mRNA: an independent prognostic variable in completely resected chemonaive NSCLC patients ERCC1l Essential component of NERl Assessed by: Functional germ-line polymorphisms Expression levels by mRNA Expressiona
10、l levels by IHCPolymorphisms of ERCC1 and survival in cisplatin treated NSCLC. lERCC1单核苷酸多态性预测铂类药物的疗效及患者预后 :ERCC1研究比较多的单核苷酸多态性位点主要是Asn118Asn （C/T），第118位密码子的同义突变。携带有C/C基因型的非 小细胞肺癌患者对铂类化疗疗效比携带T/T 或C/T 基因型患者好，总体生存的时间长。 lAsn118Asn（C/T）单核苷酸位点在不同人种中分布不同，这可能是解释不同的研究小组在不同人种中所做研究结果不同。 在亚洲人种中，目前发表的研究结果支持C/C基因
11、型是预测铂类敏感的指标。 Isla, Sarries et al.; Ann Oncol, 2004 ERCC1 mRNA levels in advanced NSCLC treated with gemcitabine-cisplatin.l56 patients with advanced NSCLC.lLow vs high ERCC1 mRNA RR: 52% and 36% (p = NS), MS: 15 months and 5 months (P 55lFor the study population as a whole, ERCC1 had no prognostic v
12、alue.lOlaussen, Dunant et al.; N Engl J Med, 2006Olaussen, Dunant et al.; N Engl J Med, 2006ERCC1阴性的患者术后辅助铂类联合化疗 能明显提高患者的生存（OR 0.65; 95% CI: 0.50-0.86; p=0.002）， 然而ERCC1阳性的患者对术后含铂类方案 却不能获益（OR 1.14; 95% CI: 0.84-1.55; p=0.40）。 Low genotypic group docetaxel / cisplatinHigh genotypic groupdocetaxel / g
13、emcitabine R A N D O M I Z EGenotypic arm ERCC1 levels1:2docetaxel / cisplatinControl armlow ERCC1 mRNAhigh ERCC1 mRNACustomizing cisplatin-based chemotherapy on quantitative ERCC1 mRNA expression: a phase III randomized trial in NSCLCCobo et al. JCO 2007Customizing cisplatin-based chemotherapy on q
14、uantitative ERCC1 mRNA expression: a phase III randomized trial in NSCLCCobo et al. JCO 2007IALT Bio (Olaussen et al, NEJM 06)ERCC1 is a prognostic factor in CT-nave patientsTumor tissue availableTumor tissue not availableNever smokerSmokerEGFR mutationserlotinibmRNA levels (QPCR)BRCA1ERCC1 MZF1 MAD
15、2 BubR1Q1 gem/cisQ2 25:2735-2740 2007Fig 2. Kaplan-Meier analyses of overall survival according to treatment (A) in patients with p27Kip1-negative tumors and (B) in patients with p27Kip1-positive tumorsNSCLC patients with p27-negative tumors benefit from adjuvant cisplatin-based chemotherapyPrognost
16、ic and Predictive Importance of p53 and RAS for Adjuvant Chemotherapy in Non Small-Cell Lung Cancer lthe prognostic and predictive value of p53 gene/protein aberrations using tumor samples from JBR.10, a North American phase III intergroup trial that randomly assigned 482 patients with completely resected stage IB and II nonsmall-cell lung cancer (NSCLC) to receive four cycles of adjuvant cisp
