本帖最后由 mindfury 于 2014-3-23 15:12 编辑
AZD9291耐药的癌细胞对elumetinib (AZD6244，MEK抑制剂）敏感，两者联用有可能延迟肿瘤耐药的发生。
#1722 Investigating resistance to AZD9291.
Cath Eberlein,1 Laura Ratcliffe,2 Lucy O'Brien,2 Katie Al-Khadimi,1 Henry Brown,1 Paul Fisher,1 Daniel Stetson,3 Zhongwu Lai,3 Gayle Marshall,1 Claire Barnes,1 Kenneth Thress,3 Brian Dougherty,3 William Pao,4 Darren Cross1. 1AstraZeneca, Cheshire, United Kingdom; 2Former employee of Astrazeneca, Cheshire, United Kingdom; 3AstraZeneca, Waltham, Boston, MA; 4Vanderbilt University, Nasville, TN.
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. |
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