Abstract
Glioblastoma multiforme (GBM) is one of the most recalcitrant brain tumors characterized by a tumor microenvironment (TME) that strongly supports GBM growth, aggressiveness, invasiveness, and resistance to therapy. Importantly, a common feature of GBM is the aberrant activation of receptor tyrosine kinases (RTKs) and of their downstream signaling cascade, including the non-receptor tyrosine kinase SRC. SRC is a central downstream intermediate of many RTKs, which triggers the phosphorylation of many substrates, therefore, promoting the regulation of a wide range of different pathways involved in cell survival, adhesion, proliferation, motility, and angiogenesis. In addition to the aforementioned pathways, SRC constitutive activity promotes and sustains inflammation and metabolic reprogramming concurring with TME development, therefore, actively sustaining tumor growth. Here, we aim to provide an updated picture of the molecular pathways that link SRC to these events in GBM. In addition, SRC targeting strategies are discussed in order to highlight strengths and weaknesses of SRC inhibitors in GBM management, focusing our attention on their potentialities in combination with conventional therapeutic approaches (i.e., temozolomide) to ameliorate therapy effectiveness.
Highlights
Glioblastoma multiforme (GBM) is the most common and lethal primary malignant cancer of the central nervous system (CNS)
Genomic and transcriptomic analysis have identified the deregulation of TP53, RB1, and receptor tyrosine kinases (RTK)/Ras/PI3K pathway as very highly frequent, and have pointed to these signaling as a core requirement for GBM pathogenesis [3]
Genome-wide studies have identified the aberrant functionality of RTKs as a main feature of GBM [3] and among them, epidermal growth factor receptor (EGFR) is constitutively activated in about 57% of GBM
Summary
Glioblastoma multiforme (GBM) is the most common and lethal primary malignant cancer of the central nervous system (CNS). Genomic and transcriptomic analysis have identified the deregulation of TP53, RB1, and receptor tyrosine kinases (RTK)/Ras/PI3K pathway as very highly frequent, and have pointed to these signaling as a core requirement for GBM pathogenesis [3]. The aberrant activation of RTKs results in deregulation of their downstream signaling cascade which includes activation of MAPK and ERK pathways, as well as activation of non-receptor tyrosine kinases, such as SRC and ABL [4]. The main resistance mechanisms are again associated with tumor heterogenicity and evolution, sustained inflammatory cytokines production, rewiring of the metabolism, and with aberrant functionality of DNA damage response and DNA repair mechanisms [8,9,10,11]. Being the hyperactivation of SRC kinase a central node downstream the constitutive activation of RTKs, we aim here to discuss its possible significance in GBM. We discuss the significance and the concerns about SRC targeting as a valuable therapeutic strategy
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