Dual MET-EGFR combinatorial inhibition against T790M-EGFR-mediated erlotinib-resistant lung cancer.
Dual MET-EGFR combinatorial inhibition against T790M-EGFR-mediated erlotinib-resistant lung cancer.
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DOI：
10.1038/sj.bjc.6604559
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发表时间：
2008-09-16
影响因子：
8.8
通讯作者：
Ma, P. C.
中科院分区：
文献类型：
--
作者：
Tang, Z.;Du, R.;Jiang, S.;Wu, C.;Barkauskas, D. S.;Richey, J.;Molter, J.;Lam, M.;Flask, C.;Gerson, S.;Dowlati, A.;Liu, L.;Lee, Z.;Halmos, B.;Wang, Y.;Kern, J. A.;Ma, P. C.
尽管埃洛替尼在临床上得到了批准，但大多数晚期肺癌患者都是主要的无反应者。最初的应答者总是发生继发性耐药，这可以由T790M-EGFR突变在一半的复发中解释。我们发现MET在肺癌中高表达，通常伴随着表皮生长因子受体(EGFR)，包括H1975细胞系。用顺式表达L858R/T790M-EGFR的耐药肺癌细胞株H1975，检测小分子抑制剂SU11274对MET的抑制作用。H1975细胞表达野生型MET，无基因组扩增(CNV=1.1)。在2 μM时，SU11274对H1975细胞有明显的促凋亡作用，是厄洛替尼的3.9倍(P=0.0015)，但对MET和EGFR阴性的H520细胞没有影响。在体内，在我们的生物发光分子成像分析中，SU11274还诱导了H1975小鼠移植瘤细胞的显著减少。使用小动物microPET/MRI，SU11274治疗被发现在H1975肿瘤异种移植瘤中诱导早期肿瘤代谢反应。在野生型(A549)和L858R/T790M-EGFR(H1975)中，MET和EGFR通路表现出协同信号和受体交叉激活的不同模式。SU11274联合厄洛替尼/CL-387,785可增强MET对下游细胞增殖存活信号的抑制作用。在H1975细胞中单独使用针对MET的siRNA、单独使用EGFR或同时使用两者的击倒研究证实，双重MET-EGFR信号通路抑制增强了下游抑制。最后，在我们的延时视频显微镜和体内多模式分子成像研究中，双重SU11274-erlotinib同时治疗有效地抑制了H1975细胞，增强了细胞骨架功能，并完全逆转了异种移植瘤的生长。综上所述，我们的结果表明，使用小分子MET抑制剂的MET靶向抑制可以成为T790M-EGFR介导的厄洛替尼耐药非小细胞肺癌的潜在治疗策略。此外，MET抑制结合厄洛替尼或不可逆的EGFR-TKI可进一步实现最佳抑制。
Despite clinical approval of erlotinib, most advanced lung cancer patients are primary non-responders. Initial responders invariably develop secondary resistance, which can be accounted for by T790M-EGFR mutation in half of the relapses. We show that MET is highly expressed in lung cancer, often concomitantly with epidermal growth factor receptor (EGFR), including H1975 cell line. The erlotinib-resistant lung cancer cell line H1975, which expresses L858R/T790M-EGFR in-cis, was used to test for the effect of MET inhibition using the small molecule inhibitor SU11274. H1975 cells express wild-type MET, without genomic amplification (CNV=1.1). At 2 μM, SU11274 had significant in vitro pro-apoptotic effect in H1975 cells, 3.9-fold (P=0.0015) higher than erlotinib, but had no effect on the MET and EGFR-negative H520 cells. In vivo, SU11274 also induced significant tumour cytoreduction in H1975 murine xenografts in our bioluminescence molecular imaging assay. Using small-animal microPET/MRI, SU11274 treatment was found to induce an early tumour metabolic response in H1975 tumour xenografts. MET and EGFR pathways were found to exhibit collaborative signalling with receptor cross-activation, which had different patterns between wild type (A549) and L858R/T790M-EGFR (H1975). SU11274 plus erlotinib/CL-387,785 potentiated MET inhibition of downstream cell proliferative survival signalling. Knockdown studies in H1975 cells using siRNA against MET alone, EGFR alone, or both, confirmed the enhanced downstream inhibition with dual MET–EGFR signal path inhibition. Finally, in our time-lapse video-microscopy and in vivo multimodal molecular imaging studies, dual SU11274-erlotinib concurrent treatment effectively inhibited H1975 cells with enhanced abrogation of cytoskeletal functions and complete regression of the xenograft growth. Together, our results suggest that MET-based targeted inhibition using small-molecule MET inhibitor can be a potential treatment strategy for T790M-EGFR-mediated erlotinib-resistant non-small-cell lung cancer. Furthermore, optimised inhibition may be further achieved with MET inhibition in combination with erlotinib or an irreversible EGFR-TKI.
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影响因子：
11.2
作者：
Mulloy, Roseann;Ferrand, Audrey;Settleman, Jeffrey
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Settleman, Jeffrey
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