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Updated: Oct 30, 2025

Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
Published on: August 11, 2017
EGFR in Cancer: Signaling Mechanisms, Drugs, and Acquired Resistance
Mary Luz Uribe1, Ilaria Marrocco1, Yosef Yarden1
1Department of Biological Regulation, Weizmann Institute of Science, Rehovot 7610001, Israel.
Abstract:
The epidermal growth factor receptor (EGFR) has served as the founding member of the large family of growth factor receptors harboring intrinsic tyrosine kinase function. High abundance of EGFR and large internal deletions are frequently observed in brain tumors, whereas point mutations and small insertions within the kinase domain are common in lung cancer. For these reasons EGFR and its preferred heterodimer partner, HER2/ERBB2, became popular targets of anti-cancer therapies. Nevertheless, EGFR research keeps revealing unexpected observations, which are reviewed herein. Once activated by a ligand, EGFR initiates a time-dependent series of molecular switches comprising downregulation of a large cohort of microRNAs, up-regulation of newly synthesized mRNAs, and covalent protein modifications, collectively controlling phenotype-determining genes. In addition to microRNAs, long non-coding RNAs and circular RNAs play critical roles in EGFR signaling. Along with driver mutations, EGFR drives metastasis in many ways. Paracrine loops comprising tumor and stromal cells enable EGFR to fuel invasion across tissue barriers, survival of clusters of circulating tumor cells, as well as colonization of distant organs. We conclude by listing all clinically approved anti-cancer drugs targeting either EGFR or HER2. Because emergence of drug resistance is nearly inevitable, we discuss the major evasion mechanisms.
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