The resistance mechanisms and treatment strategies for EGFR-mutant advanced non-small-cell lung cancer

Wen-Zhao Zhong, Qing Zhou and Yi-Long Wu _

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Oncotarget. 2017; 8:71358-71370. https://doi.org/10.18632/oncotarget.20311

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Wen-Zhao Zhong1, Qing Zhou1 and Yi-Long Wu1

1Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou 510080, China

Correspondence to:

Yi-Long Wu, email: [email protected]

Keywords: EGFR mutation, advanced NSCLC, EGFR-TKIs resistance mechanism, precision medicine

Received: May 04, 2017     Accepted: August 06, 2017     Published: August 17, 2017


Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) have been established as the standard therapy for EGFR-sensitizing mutant advanced non-small-cell lung cancer (NSCLC). However, patients ultimately develop resistance to these drugs. There are several mechanisms of both primary and secondary resistance to EGFR-TKIs. The primary resistance mechanisms include point mutations in exon 18, deletions or insertions in exon 19, insertions, duplications and point mutations in exon 20 and point mutation in exon 21 of EGFR gene. Secondary resistance to EGFR-TKIs is due to emergence of T790M mutation, activation of alternative signaling pathways, bypassing downstream signaling pathways and histological transformation. Strategies to overcome these intrinsic and acquired resistance mechanisms are complex. With the development of the precision medicine for advanced NSCLC, available systemic and local treatment options have expanded, requiring new clinical algorithms that take into account resistance mechanism. Though combination therapy is emerging as the standard of to overcome resistance mechanisms. Personalized treatment modalities based on molecular diagnosis and monitoring is essential for disease management. Emerging data from the ongoing clinical trials on combination therapy of third generation TKIs and antibodies in EGFR mutant NSCLC are promising for better survival outcomes.

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