Targeting the complexity of Src signalling in the tumour microenvironment of pancreatic cancer: from mechanism to therapy

Abstract

Pancreatic cancer, a disease with extremely poor prognosis, has been notoriously resistant to virtually all forms of treatment. The dynamic crosstalk that occurs between tumour cells and the surrounding stroma, frequently mediated by intricate Src/FAK signalling, is increasingly recognised as a key player in pancreatic tumourigenesis, disease progression and therapeutic resistance. These important cues are fundamental for defining the invasive potential of pancreatic tumours, and several components of the Src and downstream effector signalling have been proposed as potent anticancer therapeutic targets. Consequently, numerous agents that block this complex network are being extensively investigated as potential antiinvasive and antimetastatic therapeutic agents for this disease. In this review, we will discuss the latest evidence of Src signalling in PDAC progression, fibrotic response and resistance to therapy. We will examine future opportunities for the development and implementation of more effective combination regimens, targeting key components of the oncogenic Src signalling axis, and in the context of a precision medicine‐guided approach.

Kinome Array Profiling of Patient-Derived Pancreatic Ductal Adenocarcinoma Identifies Differentially Active Protein Tyrosine Kinases

“…Our results confirm the activity of known protein tyrosine kinase-related pathways previously reported as perturbed in pancreatic cancer [ 24 , 25 , 26 , 27 , 28 ]. These results also identify protein tyrosine kinases as yet understudied or unreported in pancreatic cancer.…”

“…Because our experimental model allows us to maintain the integrity of kinase networks, our data suggest involvement of signaling pathways and regulatory cascades in pancreatic cancer pathophysiology. This study presents evidence in support of the continued development of previously established inhibitory therapeutics that target select protein kinases, such as epidermal growth factor receptor (EGFR) [ 25 ], ephrin receptor A2 (EPHA2) [ 29 ], and SRC proto-oncogene kinase (SRC) [ 27 ], and our experimental results identify new PDAC targets, such as B lymphoid kinase (BLK), lymphocyte cell-specific kinase (LCK), and ABL proto-oncogene 2 kinase (ABL2), which may play a critical role in cancer cell biochemistry or desmoplastic inflammatory cell behavior.…”

“…Several kinases consistently identified as differentially active across multiple pipelines, cell lines, or final combinatorial analyses recapitulate kinases previously identified as playing well-established roles in a variety of human cancer pathologies. These kinases include insulin receptor (INSR) kinase [ 37 , 38 ] ( Figure 2 and Figure 3 , Table 3 and Table 4 ), EPHA2 kinase [ 29 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ] ( Figure 2 and Figure 3 , Table 4 ), platelet-derived growth factor receptor alpha (PDGFRA) kinase [ 47 , 48 , 49 , 50 , 51 ] ( Figure 2 and Figure 3 , Table 1 , Table 2 , Table 3 and Table 4 ), SRC kinase [ 26 , 27 , 52 , 53 , 54 , 55 , 56 , 57 ] ( Figure 2 and Figure 3 , Table 1 , Table 2 , Table 3 and Table 4 ), and tyrosine kinase nonreceptor 2 (TNK2) kinase [ 58 , 59 , 60 , 61 , 62 , 63 , 64 ...…”

“…Of these, EPHA2 is particularly well characterized in PDAC with other groups recently presenting evidence of EPHA2-mediated drug resistance in pancreatic cancer cells [ 29 ] and proposing EPHA2 as a potential biomarker or therapeutic target in pancreatic cancer [ 29 , 40 ]. SRC, too, has a well-established evidence base supporting its role in PDAC [ 27 ]. Furthermore, many of these kinases are known to constitute important signaling axes in pancreatic cancer.…”

Identifying Drug Targets in Pancreatic Ductal Adenocarcinoma Through Machine Learning, Analyzing Biomolecular Networks, and Structural Modeling

“…Integrated genomic analysis of 456 PDAC cases identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-b, WNT, NOTCH, ROBO/SLIT signaling, G1/S transition, SWI-SNF, chromatin modification, DNA repair, and RNA processing (Bailey et al, 2016). Previous treatments for pancreatic cancer have focused on targeting some of these PDAC-associated pathways, including TGFb (Craven et al, 2016), PI3K (Conway et al, 2019), Src (Parkin et al, 2019), and RAF!MEK!ERK (Kinsey et al, 2019) and NFAT1-MDM2-MDMX (Qin et al, 2017) signaling, as well as cell-cell communication within the tumor microenvironment (Shi et al, 2019). The discovery of novel drug targets provides extremely valuable resource towards the discovery of drugs.…”