Tumor clonality and resistance mechanisms in EGFR mutation-positive non-small-cell lung cancer: implications for therapeutic sequencing. (8th November 2018)

• Record Type: Journal Article
• Authors: Kohsaka, Shinji; Petronczki, Mark; Solca, Flavio; Maemondo, Makoto
• Is Part Of: Future oncology. Volume 15:Number 6(2019)
• Page Start: 637
• Page End: 652
• Publication Date: 2018-11-08
• Subjects: acquired resistance -- afatinib -- clonal evolution -- EGFR -- erlotinib -- gefitinib -- NSCLC -- osimertinib; Oncology -- Periodicals; 616.99405
• DOI: 10.2217/fon-2018-0736
• Languages: English
• ISSNs: 1479-6694

Abstract

While the development of EGFR-targeted tyrosine kinase inhibitors (TKIs) has revolutionized treatment of EGFR mutation-positive non-small-cell lung cancer, acquired resistance to therapy is inevitable, reflecting tumor evolution. Recent studies show that EGFR mutation-positive non-small-cell lung cancer is highly heterogeneous at the cellular level, facilitating clonal expansion of resistant tumors via multiple molecular mechanisms. Here, we review the mechanistic differences between first-, second- and third-generation EGFR-targeted TKIs and speculate how these features could explain differences in clinical activity between these agents from a clonal evolution perspective. We hypothesize that the molecular dissection of tumor resistance mechanisms will facilitate optimal sequential use of EGFR TKIs in individual patients, thus maximizing the duration of chemotherapy-free treatment and survival benefit. Graphical abstract: