目前最全EGFR耐药机制总结

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本帖最后由 longyangagent 于 2016-4-15 19:28 编辑

http://www.ncbi.nlm.nih.gov/pubmed/26579470 Acta Pharm Sin B.
2015 Sep;5(5):390-401. doi: 10.1016/j.apsb.2015.07.001. Epub 2015 Jul 26.
Mechanisms of resistance to EGFR tyrosine kinase inhibitors.
1、EGFR突变信号通路

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2、EGFR二次突变，主要是T790M,其次是 L747S, D761Y and T854A
3、旁通信号bypass
3.1  HER 其他家族成员的异常
3.2 CMT扩增
3.3 HGF过表达
3.4 IGFR异常
3.5 异常血管生长通路
3.5.1 VEGFs 及其受体
3.5.2  FGFs 及其受体
  3.5.3.  PDGFRs及其受体
3.6. EGFRvIII
3.7. AXL过表达
3.8. IL-6过分泌
3.9. Amplification of Crk-like protein (CRKL扩增)
3.10. Overexpression and activation of integrin beta1-整合素β1的过表达和激活
4、异常下游信号
4.1. K-RAS 突变
4.2.  PTEN丢失
4.3. BRAF突变
4.4.  PIK3CA突变
4.5. NF1异常表达
5. BIM损伤
6、组织类型的变化
6.1. EMT
6.2小细胞肺癌转换
7. ATP binding cassette (ABC) effusion
8. EML4-ALK融合基因和二次突变
9。治疗策略：联合治疗

Resistant mechanism
耐药机制 Strategy
治疗策略 Clinical research
临床研究 Ref.
参考文献
EGFRmutation
T790M EGFR-TKIs combined/+antibodies Afatinib+cexitumab 80
T790M-specific inhibitors CO-1686/AZD9291 81, 82
c-Met inhibitors+PI3K inhibitors GDC0973+GDC0941 83
HSP90 inhibitors Luteolin/ganetespib 11, 84
EGFR-TKIs+MEK inhibitors Afatinib+ARQ 197 85
Glycolysis inhibition+EGFR-TKIs Afatinib+AUY922 86
Bypass pathway
HER family abnormality HER inhibitors+EGFR-TKIs Afatinib/dacomitinib 18, 87
c-Met amplification EGFR-TKIs+c-Met inhibitors Erlotinib+crizotinib 88
Dacomitinib+crizotinib
HGF overexpression EGFR-TKIs+PI3K inhibitors Gefitinib+PI-103 89
Triple inhibition of EGFR/Met/VEGF – 90
IGFR abnormality IGFR inhibitors+EGFR-TKIs AG1024+gefitinib –
EGFRvIII EGFRvIII antibodies – –
VEGF/VEGFR abnormality EGFR-TKIs+VEGF inhibitors ZD6474 91
MEK inhibitors+VEGF inhibitors ZD6474+PD0325901 30
PDGF/PDGFR abnormality EGFR-TKIs+PDGF inhibitors – –
FGF/FGFR abnormality EGFR-TKIs+FGF inhibitors – –
IL-6 abnormality IL-6 antibodies Siltuximab 92
AXL abnormality AXL inhibitors NPS-1034 93
CRKL amplification Unknown Unknown –
Integrin beta1 overexpression Unknown Unknown –
Downstream pathway
K-RAS mutations PI3K inhibitors+MEK inhibitors GDC-0941+AZD6244 94
BRAF mutations BRAF inhibitors+MEK inhibitors Dabrafenib+trametinib 95
Loss of PTEN mTOR inhibitors/AKT
inhibitors – –
PIK3CA mutation EGFR-TKIs+PI3K inhibitors Gefitinib+BKM120 96
Low expression of NF1 Unknown Unknown –
Apoptosis pathway
BIM BH3 deletion EGFR-TKIs+PP2A activator Erlotinib+FTY720 gefitinib+FTY720 62
Histologic transformation
EMT EGFR-TKIs+MEK1/2 inhibitors – –
SCLC transformation Platinum+VP16/EGFR-TKIs – –
ABC effusion EGFR-TKIs+HER-2 inhibitors GW583340/GW2974 73

Unknown mechanism EGFR-TKIs combined Afatinib+cexitumab 80
EGFR-TKIs+glycolysis inhibitors Erlotinib+AUY922
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