Format

Send to

Choose Destination
Cancer Lett. 2016 Oct 1;380(2):494-504. doi: 10.1016/j.canlet.2016.07.021. Epub 2016 Jul 19.

Met gene amplification and protein hyperactivation is a mechanism of resistance to both first and third generation EGFR inhibitors in lung cancer treatment.

Author information

1
Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi, China; Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
2
Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
3
Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
4
Department of Medical Oncology and Therapeutic Research, City of Hope, Duarte, CA, USA.
5
Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi, China. Electronic address: chenmingwei@mail.xjtu.edu.cn.
6
Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA. Electronic address: ssun@emory.edu.

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.

KEYWORDS:

AZD9291; Bim; EGFR; Erlotinib; Met; Resistance

PMID:
27450722
DOI:
10.1016/j.canlet.2016.07.021
[Indexed for MEDLINE]

MeSH terms, Substances, Grant support

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center