抗肿瘤靶向药物研究进展演示文稿.ppt

* ABC 转运泵过表达 * ABC 转运泵泵出EGFR-TKIs TKI能诱导ABC转运泵过表达 过表达的ABC转运泵能外排TKI * Lapatinib activates the ATPase activity of ABCB1 or ABCG2 Lapatinib significantly stimulates the ATPase activities of ABCB1 and ABCG2 at low concentrations. ABCB1 ABCG2 TKIs 为ABC转运泵底物 * 0 0.3 0.6 1.3 2.5 5.0 10 20 40 IC50 = 3.20 ± 1.13 (μM) Lapatinib (μM) 0 1.3 2.5 5.0 10 20 40 80 100 IC50 = 2.79 ± 0.60 (μM) Lapatinib binded to both the ABCB1 and ABCG2 substrate-binding sites with high affinity. Lapatinib affects the photo-labeling of ABCB1 and ABCG2 with [125I]-IAAP ABCB1 ABCG2 * TKIs与ABC转运泵交互作用 Some TKIs inhibited the function of ABC transporters and enhanced the efficacy of substrate-chemotherapeutical agents Fu LW, et al. Cancer Res, 2011, 71(8):3029-41 ; 2011;71(11):3735-8 (Review). Fu LW, et al. Br J Pharmacol. 2012 Jan 10. doi: 10.1111/j.1476-5381.2012.01849.x. Fu LW, et al. Biochem Pharmacol. 2011 Dec 16. [Epub ahead of print] Fu LW, et al. Eur J Cancer. 2011;47(13):1990-9. * NSCLC对EGFR-TKIs耐药机理 EGFR的第二次突变（T790M） 冗余激酶的激活 下游通路异常（K-ras突变、PTEN ) EMT ABC transporters 其他 * Nature Reviews Cancer, 2011 克服EGFR耐药的治疗策略——同时靶向多条通路 * 基于耐药机制的临床试验 机制 策略 临床研究 T790M 联合使用EGFR抑制剂 Afatinib+C225 T790M特异性抑制剂 CO-1686、AP26113 C-Met抑制剂+PI3k抑制剂 GDC0973+GDC0941 Hsp90抑制剂 AUY922 C-Met扩增 EGFR抑制剂+c-Met抑制剂 Erlotinib+Crizotinib Dacomitinib+Crizotinib SCLC转化 铂类+VP16+/-EGFR-TKI / PIK3CA EGFR+PI3K抑制剂 Gefitinib+BKM120 未知机理 EGFR-TKI联合Hsp90抑制剂 Afatinib+C225 Erlotinib+AUY922 * EGFR-TKI治疗 NSCLC失败 爆发进展 疾病控制3个月 与以往评估相比， 肿瘤负荷快速增加 症状评分=2 缓慢进展 疾病控制6个月 与以往评估相比， 肿瘤负荷轻微增加 症状评分1 局部进展 疾病控制3个月 孤立性颅外或颅 内进展 症状评分1 化疗 持续TKI+/-化疗 持续TKI+局部治疗 * 谢 谢！ - The ITT analysis showed a statistically significantly longer median time to progression (4.1 versus 1.5 months, p0.001) for the ERBITUX plus irinotecan combination compared with ERBITUX monotherapy. - The hazard ratio for disease progression in the combination therapy group as compared with the monotherapy group was 0.54, indicating a 46% reduction in the