1. Met gene amplification and protein hyperactivation is a mechanism of resistance to both first and third generation EGFR inhibitors in lung cancer treatment.
- Author
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Shi, Puyu, Oh, You-Take, Zhang, Guojing, Yao, Weilong, Yue, Ping, Li, Yikun, Kanteti, Rajani, Riehm, Jacob, Salgia, Ravi, Owonikoko, Taofeek K., Ramalingam, Suresh S., Chen, Mingwei, and Sun, Shi-Yong
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LUNG cancer treatment , *LUNG cancer & genetics , *GENE amplification , *MET gene , *EPIDERMAL growth factor receptors , *ACRYLAMIDE , *AMINES , *ANTHROPOMETRY , *ANTINEOPLASTIC agents , *APOPTOSIS , *CELL lines , *CELL physiology , *CELLULAR signal transduction , *DRUG therapy , *DRUG resistance in cancer cells , *DOSE-effect relationship in pharmacology , *EPIDERMAL growth factor , *GENES , *GENETIC techniques , *HETEROCYCLIC compounds , *LUNG cancer , *LUNG tumors , *MICE , *GENETIC mutation , *PYRIDINE , *RESEARCH funding , *TIME , *PROTEIN kinase inhibitors , *CHEMICAL inhibitors , *PHARMACODYNAMICS - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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