EGFR in Cancer: Signaling Mechanisms, Drugs, and Acquired Resistance.

Abstract

Simple SummaryGrowth factors are hormone-like molecules able to promote division and migration of normal cells, but cancer captured the underlying mechanisms to unleash tumor growth and metastasis. Here we review the epidermal growth factor (EGF), which controls epithelial cells, the precursors of all carcinomas, and the cognate cell surface receptor, called EGFR. In addition to over-production of EGF and its family members in tumors, EGFR is similarly over-produced, and mutant hyper-active forms of EGFR are uniquely found in some brain, lung, and other cancers. After describing the biochemical mechanisms underlying the cancer-promoting actions of EGFR, we review some of the latest research discoveries and list all anti-cancer drugs specifically designed to block the EGFR’s biochemical pathway. We conclude by explaining why some patients with lung or colorectal cancer do not respond to the anti-EGFR therapies and why still other patients, who initially respond, become tolerant to the drugs.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.