Met gene amplification and protein hyperactivation is a mechanism of resistance to both first and third generation EGFR inhibitors in lung cancer treatment
Met gene amplification and protein hyperactivation is a mechanism of resistance to both first and third generation EGFR inhibitors in lung cancer treatment
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DOI：
10.1016/j.canlet.2016.07.021
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发表时间：
2016-10-01
期刊：
影响因子：
9.7
通讯作者：
Sun, Shi-Yong
中科院分区：
文献类型：
--
作者：
Shi, Puyu;Oh, You Take;Sun, Shi-Yong
第三代表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI;例如，AZD 9291），选择性和不可逆地抑制EGFR激活和T790 M突变体，代表了非常有前途的治疗选择的非小细胞肺癌（NSCLC）患者已成为耐药的第一代EGFR-TKI由于T790 M突变。然而，临床上已经描述了对第三代EGFR-TKI的最终耐药性，导致疾病进展。因此，了解这种耐药性是如何发生的，并制定有效的策略来延缓或克服耐药性，是一个巨大的挑战和迫切需要。目前的研究表明，Met扩增和超活化是第一代和第三代EGFR-TKI的耐药机制，因为厄洛替尼和AZD 9291耐药HCC 827细胞系均具有扩增的Met基因和超活化的Met，并且对AZD 9291或厄洛替尼交叉耐药。Met抑制克服了这些细胞系在体外和体内对AZD 9291的抗性，包括增强凋亡或G1细胞周期阻滞。因此，我们认为Met抑制也是克服某些具有Met扩增的EGFR突变NSCLC对AZD 9291耐药性的有效策略，从而进一步验证我们的发现。(C)2016爱思唯尔爱尔兰有限公司版权所有。
The 3rd generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs; e.g., AZD9291), which selectively and irreversibly inhibit EGFR activating and T790M mutants, represent very promising therapeutic options for patients with non-small cell lung cancer (NSCLC) that has become resistant to 1st generation EGFR-TKIs due to T790M mutation. However, eventual resistance to the 3rd generation EGFR-TKIs has already been described in the clinic, resulting in disease progression. Therefore, there is a great challenge and urgent need to understand how this resistance occurs and to develop effective strategies to delay or overcome the resistance. The current study has demonstrated that Met amplification and hyperactivation is a resistance mechanism to both 1st and 3rd generation EGFR-TKIs since both erlotinib- and AZD9291-resistant HCC827 cell lines possessed amplified Met gene and hyperactivated Met, and were cross-resistant to AZD9291 or erlotinib. Met inhibition overcame the resistance of these cell lines to AZD9291 both in vitro and in vivo, including enhancement of apoptosis or G1 cell cycle arrest. Hence, we suggest that Met inhibition is also an effective strategy to overcome resistance of certain EGFR-mutated NSCLCs with Met amplification to AZD9291, warranting the further clinical validation of our findings. (C) 2016 Elsevier Ireland Ltd. All rights reserved.