c-Src and EGFR Inhibition in Molecular Cancer Therapy: What Else Can We Improve?

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.

Development of the phenylpyrazolo[3,4-d]pyrimidine-based, insulin-like growth factor receptor/Src/AXL-targeting small molecule kinase inhibitor

“…In line with the findings, PC9/ER cells showed resistance to the corresponding EGFR TKI after a prolonged culture in the absence of drug for more than a month ( Figure S5 ). PC9/ER and PC9 cells were further analyzed for activation status of several RTKs [MET, IGF-1R, and AXL], a nonreceptor tyrosine kinase Src, and IGFBP-3, all of which have been implicated in resistance to EGFR TKIs 49 , 50 . We observed greater activation of IGF-1R, Src, and AXL and weaker expression of IGFBP-3 in PC9/ER than in PC9 cells ( Figure 2 C ).…”

Study on the effects of Polyphyllin I and Curcumin on liver cancer based on the cross-action of ferroptosis and energy metabolism

“…There are currently 11 family members discovered, and Src is currently one of the most studied members [23]. Src consists of SH4 domain, speci c fragments, SH3 domain, SH2 domain, linker, SH1 domain (protein tyrosine kinase domain) and carboxy-terminal regulatory tail [24].…”

Pathway profiling of a novel SRC inhibitor, AZD0424, in combination with MEK inhibitors

“…While SRC is rarely mutated in cancer, it often functions downstream of oncogenic drivers in signalling cascades including those initiated by receptor tyrosine kinases (RTKs) and at integrin-linked focal adhesions (4). SRC has been a target for drug discovery projects for decades with multiple small molecule ATP-competitive inhibitors being tested in clinical trials (2, 5-11). Dasatinib, a multi-kinase SRC inhibitor, is currently approved for the treatment of chronic myeloid and acute lymphoblastic leukaemias (12).…”