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Med Res Rev. 2018 Sep;38(5):1550-1581. doi: 10.1002/med.21488. Epub 2018 Jan 26.

Targeting EGFRL858R/T790M and EGFRL858R/T790M/C797S resistance mutations in NSCLC: Current developments in medicinal chemistry.

Author information

1
School of Pharmacy, Jinan University, Guangzhou, China.
2
Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
3
Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.
4
Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand.

Abstract

Both the first-generation reversible epidermal growth factor receptor (EGFR) inhibitors gefitinib and erlotinib and the second-generation covalent epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) afatinib have significantly improved the survival of non-small-cell lung cancer (NSCLC) patients with activating EGFR mutations. However, a secondary EGFRT790M mutation leads to the clinically acquired resistance to the first- and second-generation EGFR-TKIs drugs. A number of the third-generation wild-type sparing EGFR inhibitors, for example, WZ4002, CO1686, AZD9291, HM61713, EGF816, ASP8173, and PF0674775, have been developed, among which AZD9291 has been approved by US FDA for the treatment of NSCLC patients with EGFRT790M . More recently, a tertiary EGFRC797S mutation was reported as the dominant resistance mechanism to the third-generation irreversible inhibitors. It is highly desirable to develop the fourth-generation EGFR inhibitors. This review summarizes the mechanisms of acquired resistance and the latest medicinal chemistry advances on the third- and fourth-generation EGFR inhibitors, with special attention being paid to the allosteric and reversible inhibitors combating the tertiary EGFRC797S mutation.

KEYWORDS:

EGFRC797S; EGFRT790M; resistance mutation; the fourth-generation inhibitors; the third-generation inhibitors

PMID:
29377179
DOI:
10.1002/med.21488
[Indexed for MEDLINE]

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