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.
Highlights
Because epidermal growth factor receptor (EGFR) has been the pioneer member of the receptor tyrosine kinase family, and many lines of evidence linked this receptor, its growth factor ligands, and co-receptors to human malignancies, EGFR research has paved the way to several important concepts in cancer progression
Along with sustaining cell proliferation and conferring resistance to anti-cancer cytotoxic drugs, EGFR strongly promotes metastasis through a large collection of paracrine loops, each controlling a critical step of the metastasis cascade
We have learned that the response to EGFR activation is surprisingly reproducible, highly ordered, and time-dependent: wave-like epigenetic events precede and license long-term commitments to specific cell fates
Summary
University by Viktor Hamburger, one of the fathers of developmental neuroscience, assumed that the growth of nerve cells depended on an inductive agent emanating from their destination. To test this hypothesis, Hamburger removed developing limb buds from chick embryos and tested whether nerve cells near the spinal cord would still grow toward the limb. Unlike EGFR and both HER3 and HER4, which bind neuregulins (NRGs), HER2 binds with no known growth factor This receptor acts as an amplifier of growth factor signals, in the context of a layered signaling network [7]. The reader is referred to similar reviews covering additional aspects of EGFR and the three other type I RTKs [8,9]
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