Acquired resistance to third-generation EGFR-TKIs and emerging next-generation EGFR inhibitors

Xiaojing Du; Biwei Yang; Quanlin An; Yehuda G Assaraf; Xin Cao; Jinglin Xia

doi:10.1016/j.xinn.2021.100103

Acquired resistance to third-generation EGFR-TKIs and emerging next-generation EGFR inhibitors

Innovation (Camb). 2021 Apr 3;2(2):100103. doi: 10.1016/j.xinn.2021.100103. eCollection 2021 May 28.

Authors

Xiaojing Du^{1

2

3}, Biwei Yang^{1

2}, Quanlin An¹, Yehuda G Assaraf⁴, Xin Cao¹, Jinglin Xia^{1

2

3

5}

Affiliations

¹ Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
² Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
³ Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai 201199, China.
⁴ The Fred Wyszkowski Cancer Research Lab, Department of Biology, Technion-Israel Institute of Technology, Haifa 3200000, Israel.
⁵ The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.

Abstract

The discovery that mutations in the EGFR gene are detected in up to 50% of lung adenocarcinoma patients, along with the development of highly efficacious epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), has revolutionized the treatment of this frequently occurring lung malignancy. Indeed, the clinical success of these TKIs constitutes a critical milestone in targeted cancer therapy. Three generations of EGFR-TKIs are currently approved for the treatment of EGFR mutation-positive non-small cell lung cancer (NSCLC). The first-generation TKIs include erlotinib, gefitinib, lapatinib, and icotinib; the second-generation ErbB family blockers include afatinib, neratinib, and dacomitinib; whereas osimertinib, approved by the FDA on 2015, is a third-generation TKI targeting EGFR harboring specific mutations. Compared with the first- and second-generation TKIs, third-generation EGFR inhibitors display a significant advantage in terms of patient survival. For example, the median overall survival in NSCLC patients receiving osimertinib reached 38.6 months. Unfortunately, however, like other targeted therapies, new EGFR mutations, as well as additional drug-resistance mechanisms emerge rapidly after treatment, posing formidable obstacles to cancer therapeutics aimed at surmounting this chemoresistance. In this review, we summarize the molecular mechanisms underlying resistance to third-generation EGFR inhibitors and the ongoing efforts to address and overcome this chemoresistance. We also discuss the current status of fourth-generation EGFR inhibitors, which are of great value in overcoming resistance to EGFR inhibitors that appear to have greater therapeutic benefits in the clinic.

Keywords: Cancer; EGFR inhibitors; chemoresistance mechanisms; drug resistance; mutations; surmounting chemoresistance; targeted therapy.

Publication types

Review