Receptor tyrosine kinase signalling as a target for cancer intervention strategies.

Abstract

In multicellular organisms, communication between individual cells is essential for the regulation and coordination of complex cellular processes such as growth, differentiation, migration and apoptosis. The plethora of signal transduction networks mediating these biological processes is regulated in part by polypeptide growth factors that can generate signals by activating cell surface receptors either in paracrine or autocrine manner. The primary mediators of such physiological cell responses are receptor tyrosine kinases (RTKs) that couple ligand binding to downstream signalling cascades and gene transcription. Investigations over the past 18 years have revealed that RTKs are not only key regulators of normal cellular processes but are also critically involved in the development and progression of human cancers. Therefore, signalling pathways controlled by tyrosine kinases offer unique opportunities for pharmacological intervention. The aim of this review is to give a broad overview of RTK signalling involved in tumorigenesis and the possibility of target-selective intervention for anti-cancer therapy.

Antagonists of growth hormone-releasing hormone inhibit growth of androgen-independent prostate cancer through inactivation of ERK and Akt kinases

“…RTKs are cell-surface receptors for many polypeptide growth factors, cytokines, and hormones (35) involved in the development and progression of various cancers (36). The PI3K/Akt/mammalian target of rapamycin (mTOR) pathway is a major signaling pathway for RTKs.…”

“…The Raf/MEK/ERK pathway, which is controlled by both GPCRs and RTKs (36), has a pivotal role in controlling cell survival, cell-cycle progression, and differentiation, and its dysregulated signaling is a central signature of many epithelial cancers, including prostate (26,40). The key effectors of this pathway, ERK1/2, are multifunctional protein kinases, which modulate gene expression through the activation of a multitude of transcription factors such as c-fos, c-myc, or NF-κβ and after translocating to the nucleus also can phosphorylate cytoplasmic and nuclear kinases (25).…”

Growth factor receptors in helminth parasites: Signalling and host–parasite relationships

“…For this reason, RTK and tyrosine kinases (TK) constitute very promising targets for chemotherapy of cancer. Progress in crystallography, in combinatorial chemistry and in high-throughput screening have led to the design of inhibitors specific for TK mutated in some cancers [60]. Structural analyses of parasite kinases indicate that they might be sufficiently different from those of the human host to permit the design of specific inhibitors able to discriminate parasite from host kinases.…”

Epidermal growth factor receptor expression correlates with poor survival in gastric adenocarcinoma from Mexican patients: a multivariate analysis using a standardized immunohistochemical detection system

“…3 Various strategies have been used to inhibit EGFR activity, targeting both extracellular or intracellular receptor components. 10,11 EGFR immunohistochemical reactivity has been investigated in colonic adenocarcinoma, and a scoring system evaluating EGFR reactivity has been proposed. 12 EGFR positivity at the invasion front showed the strongest correlation with patient survival.…”