AZD9291耐药之后的选择
本帖最后由 scrystally 于 2014-8-4 13:19 编辑链接：Investigating resistance to AZD9291
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.
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.
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.
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.
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。” 英文不懂，谁能说说 9291耐药后，用啥呢，楼主解释一下哈。 求高手翻译。 英文的看不懂啊，求高手翻译。 其实就是MEK有关系，要联合6244用的 ，只能说尝试 但貌似6244不太理想 可能要联合用 谢谢 好专业 最好有翻译成中文的 看不懂该吃啥， 耐着性子把英文看完了，貌似没有提到耐药后的选择吧，最后一句才是重点，就是中文的解释，英文差，可能看错的地方还请见谅！