Abstract
The proto-oncogene c-Src is a non-receptor tyrosine kinase playing a key role in many cellular pathways, including cell survival, migration and proliferation. c-Src de-regulation has been observed in several cancer types, making it an appealing target for drug discovery efforts. Recent evidence emphasizes its crucial role not only in promoting oncogenic traits, but also in the acquisition and maintenance of cancer resistance to various chemotherapeutic or molecular target drugs. c-Src modulates epidermal growth factor receptor (EGFR) activation and amplifies its downstream oncogenic signals. In this review, we report several studies supporting c-Src kinase role in the intricate mechanisms of resistance to EGFR tyrosine kinase inhibitors (TKIs). We further highlighted pre- and clinical progresses of combined treatment strategies made in recent years. Several pre-clinical data have encouraged the use of c-Src inhibitors in combination with EGFR inhibitors. However, clinical trials provided controversial outcomes in some cancer types. Despite c-Src inhibitors showed good tolerability in cancer patients, no incontrovertible and consistent clinical responses were recorded, supporting the idea that a better selection of patients is needed to improve clinical outcome. Currently, the identification of biological markers predictive of therapy response and the accurate molecular screening of cancer patients aimed to gain most clinical benefits become decisive and mandatory.
Highlights
SRC is a representative member of nine-gene family of non-receptor tyrosine kinases (Src FamilyKinases, SFKs) playing a key role in the modulation of several signaling pathways
We mainly describe the synergistic effect of c-Src inhibitors in combination with epidermal growth factor receptor (EGFR) inhibitors and/or with chemotherapeutic drugs on solid tumors, so that we have focused our attention on dasatinib, saracatinib and bosutinib, typically tested in lung, pancreatic, colorectal and breast cancer (Table 1)
We previously demonstrated that different c-Src inhibitors act through several mechanisms in sensitive or erlotinib-resistant non-small cell lung cancer (NSCLC) models and that the combination of c-Src or MEK inhibitors with EGFR-tyrosine kinase inhibitors (TKIs) leads to higher benefits compared to single treatment in NSCLCs
Summary
SRC is a representative member of nine-gene family of non-receptor tyrosine kinases C-Src activation induced by EGFR ligands mediates the binding of phosphatidylinositol 3-kinase (PI3K) to EGFR, leading to AKT phosphorylation and, in turn, induction of survival and migration signaling pathways [30,33,34,35,36,37]. C-Src needs the contribution of other molecules to modulate the proliferative mitogen-activated protein kinase (MAPK) pathway [18], it has been demonstrated that it can enhance EGFR ligands-induced extracellular signal-regulated protein kinase 1/2. Lin and colleagues demonstrated that digoxin, a cardiac glycoside suggested as chemo-therapeutic agent, induced decrease of c-Src, EGFR and STAT3 activation and expression and, impaired cancer cell proliferation, migration and invasion [63]. HER2 has been demonstrated by Ishizawar and colleagues, who found that the over-expression of c-Src enhances the formation and levels of HER2/HER3 heterocomplex, resulting in increased downstream signaling and biological functions (i.e., cellular motility and anchorage-independent growth) [73]
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