Mechanisms of receptor tyrosine kinase activation in cancer

Abstract

Receptor tyrosine kinases (RTKs) play an important role in a variety of cellular processes including growth, motility, differentiation, and metabolism. As such, dysregulation of RTK signaling leads to an assortment of human diseases, most notably, cancers. Recent large-scale genomic studies have revealed the presence of various alterations in the genes encoding RTKs such as EGFR, HER2/ErbB2, and MET, amongst many others. Abnormal RTK activation in human cancers is mediated by four principal mechanisms: gain-of-function mutations, genomic amplification, chromosomal rearrangements, and / or autocrine activation. In this manuscript, we review the processes whereby RTKs are activated under normal physiological conditions and discuss several mechanisms whereby RTKs can be aberrantly activated in human cancers. Understanding of these mechanisms has important implications for selection of anti-cancer therapies.

Co‐expression of EGFR and MET has a synergistic effect on the prognosis of patients with oral squamous cell carcinoma

“…RTKs are a diverse family of transmembrane proteins that relay extracellular signals into the cell and control a variety of cellular functions including proliferation, differentiation, survival, metabolism, and motility . Dysregulation of RTK function is known to disrupt intercellular and intracellular signal transduction; in addition, many RTK abnormalities have been reported in many cancer types . Most invasive HNSCC are overexpressed with EGFR, and patients with tumors that did not express EGFR had better therapeutic outcomes after a rescue surgery .…”

“…High expressions of EGFR, HER2, and FGFR1 were shown to be associated with poor prognosis of patients with HNSCC, breast and gastric cancer, and lung cancer, respectively . Du et al have discussed the mechanisms of RTK activation in cancer.…”

“…8 Dysregulation of RTK function is known to disrupt intercellular and intracellular signal transduction; in addition, many RTK abnormalities have been reported in many cancer types. 9 Most invasive HNSCC are overexpressed with EGFR, and patients with tumors that did not express EGFR had better therapeutic outcomes after a rescue surgery. 3 Currently, two types of drugs (monoclonal antibodies, such as cetuximab and nimotuzumab, and tyrosine kinase inhibitors, such as gefitinib, erlotinib, and afatinib) against EGFR have been applied in clinical practice.…”

Discoidin domain receptor 2 drives melanoma drug resistance through AXL-dependent phenotype switching

“…This resistance is associated with an increased metastasis notably due to a hyperactivation of MAP kinase activity (Sullivan and Flaherty 2013). The hyperactivation of this signaling pathway could be due to genetic events including NRAS or BRAF mutations (Wagenaar et al 2014), splice variation of BRAF, secondary mutation of MEK, overexpression of the oncoprotein BRAF or upregulation of tyrosine kinase receptors such as PDGFR, EGFR or FGFR (Basile et al 2014;Du and Lovly 2018;Nazarian et al 2010;Villanueva et al 2010;Wagenaar et al 2014).…”

Targeted RNA NextGenSeq profiling in oncology using single molecule molecular inversion probes

“…Examples are loss of function mutations in tumor suppressor genes (e.g. p53 and CDKN2A, leading to genetic instability and loss of cell cycle control) [1,2] and DNA repair proteins (leading to genetic instability) [3], and activating mutations, amplifications or fusion events in proto-oncogenes that activate the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways [4,5]. Other shared features are related to micro-environmental effectors, such as altered metabolism as a result of hypoxia [6,7] and induction of angiogenesis [8].…”