本帖最后由 草船借箭 于 2014-8-29 14:03 编辑 1 o' z) d: R+ i6 O# i
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肿瘤增殖抗原(Ki67)3 j+ n6 n# m9 T
Ki67标记的意义 & S% J( Z8 K; h" O1 B$ ^* |* W5 L" I* P
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在肿瘤病理报告中，经常会看到$ ], d; [4 [, O/ z3 _
ki67阳性细胞的比例。临床医生知道这是判断肿瘤恶性程度的，但往 & ^# |0 ^- v1 s6 t; M往并不明白其中的缘由。 ( q+ |8 g& O! D6 {3 K' C3 P9 H # i) o* O* s& \" R$ j& f
肿瘤的最大特点是生长失控。很多人误认为肿瘤的生长失控是由于细胞分裂加快、细胞周期缩短的结: H/ q, l$ U. m
果。但实际上肿瘤细胞的分裂减慢，细胞周期甚至比正常的细胞周期长，只是处于增殖期的细胞数量增多2 R. e' c2 G; E. F2 c$ ?
了，肿瘤才生长迅速，超越了周围的组织。 . [- p4 m/ ~, }9 Y9 N \$ @ E1 x) t- L3 [6 K: y
7 E) ~% l9 N" c" o在正常组织中，绝大部分细胞处于非增殖状态，细胞学上称为: P+ J1 A G& n
G0期。要构建良好的组织结构并执行特定的功能，必须依靠这些增殖周期外的% m) L' _9 A' t- b* n, w6 U0 C
G0期细胞。打个比喻，G0期的细胞就像工蜂、工蚁一样。那些9 ^6 W! X) f9 v+ c1 \
增殖的细胞就像蜂后、蚁后一般。当工蜂、工蚁的比例减少时，劳动效率必然会下降，导致组织结构不良。# i6 s, L! n, T$ |
而处于增殖状态的细胞是难以执行特定功能的，也就是常说的没有分化。# O1 G! r/ W2 m
First- and second-generation EGFR TKIs are established first line therapy for patients with NSCLC with activating mutations in EGFR. Unfortunately, patients ultimately develop disease progression with acquisition of a second-site EGFR T790M mutation in more than half of cases. This has led to the development of third generation EGFR TKIs which inhibit both the EGFRm+ and T790M mutations in preclinical models and are showing activity in TKI-resistant patients in Phase I studies. Despite the potential improvements brought by third generation EGFR-TKIs, advanced EGFRm+ tumor cells will still remain highly adaptable and the inevitability of further resistance will limit the effectiveness of these drugs. As such, the identification of resistance mechanisms to these agents is essential to guide future therapeutic strategies and identify novel:novel combinations. 3 V9 x3 Z; o* F, h) A To interrogate resistance to AZD9291, we have generated panels of EGFRm+ cell lines resistant to gefitinib (first generation TKI) and EGFRm+ and EGFRm+/T790M cell lines resistant to afatinib and AZD9291 (second and third generation TKIs, respectively). Subsequently, we characterised the cell lines using a variety of molecular profiling techniques including Next Generation Sequencing (NGS), Affymetrix gene expression analysis, and phenotypic profiling following pharmacological modulation by small molecule inhibitors of canonical signaling pathways. ( p1 c. s$ J. f. P# O- v The effects on cell survival across the range of resistant models by a panel of pathway inhibitors indicated that resistance to the EGFR inhibitors, in particular AZD9291, is frequently associated with increased sensitivity to selumetinib (AZD6244; ARRY-142886) (MEK1/2 inhibitor), suggesting that ERK signaling is commonly reactivated to circumvent inhibition of the EGFR pathway. Molecular characterisation of the panel of cell lines suggests a range of different resistance mechanisms may be responsible for reactivation of ERK signaling, including a decrease in negative regulators of ERK such as DUSP6 or an epithelial to mesenchymal transition consistent with previous observations. - A" j8 T! ?7 T: E- O Collectively, these data suggest that combining an EGFR TKI with a MEK inhibitor could prevent or delay resistance and drive superior duration of benefit from these agents. v& R0 q" w( O% x' C7 ^9 }% |$ P& V $ d+ _( b+ I$ U) t5 w总结：“总的来说，这些数据表明，联合EGFR和MEK抑制剂可以防止或推迟AZD9291的耐药，使患者从药物的获益时间增长。” # i' O% m4 X V0 v4 V5 H4 O: k8 r9 p/ u) |$ ~2 d$ t* h
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