Synergistic Anti-Tumour Effect of Syk Inhibitor and Olaparib in Squamous Cell Carcinoma: Roles of Syk in EGFR Signalling and PARP1 Activation

Abstract

Syk is a non-receptor tyrosine kinase involved in the signalling of immunoreceptors and growth factor receptors. Previously, we reported that Syk mediates epidermal growth factor receptor (EGFR) signalling and plays a negative role in the terminal differentiation of keratinocytes. To understand whether Syk is a potential therapeutic target of cancer cells, we further elucidated the role of Syk in disease progression of squamous cell carcinoma (SCC), which is highly associated with EGFR overactivation, and determined the combined effects of Syk and PARP1 inhibitors on SCC viability. We found that pharmacological inhibition of Syk could attenuate the EGF-induced phosphorylation of EGFR, JNK, p38 MAPK, STAT1, and STAT3 in A431, CAL27 and SAS cells. In addition, EGF could induce a Syk-dependent IL-8 gene and protein expression in SCC. Confocal microscopic data demonstrated the ability of the Syk inhibitor to change the subcellular distribution patterns of EGFR after EGF treatment in A431 and SAS cells. Moreover, according to Kaplan-Meier survival curve analysis, higher Syk expression is correlated with poorer patient survival rate and prognosis. Notably, both Syk and EGFR inhibitors could induce PARP activation, and synergistic cytotoxic actions were observed in SCC cells upon the combined treatment of the PARP1 inhibitor olaparib with Syk or the EGFR inhibitor. Collectively, we reported Syk as an important signalling molecule downstream of EGFR that plays crucial roles in SCC development. Combining Syk and PARP inhibition may represent an alternative therapeutic strategy for treating SCC.

Involvement of the AKT Pathway in Resistance to Erlotinib and Cabozantinib in Triple-Negative Breast Cancer Cell Lines

“…Unlike RIOK2, there is a biological rationale for the non-receptor tyrosine kinase SYK to potentially contribute to erlotinib resistance. SYK positively regulates EGFR and has been shown to be involved in EGFR signaling in squamous cells and ovarian carcinoma, where it contributes to paclitaxel and lapatinib resistance [ 78 , 79 ]. However, it has been reported that SYK possesses both tumor promoter and suppressor roles in human breast carcinoma and that decreased expression is associated with a poor prognosis [ 80 , 81 , 82 ]; thus, SYK inhibition may work either synergistically or antagonistically with erlotinib.…”

The role of dual‐specificity phosphatase 3 in melanocytic oncogenesis

“…It is shown that suppression of SYK increases EGFRderived signalling in mammary epithelial cells 63 and phosphorylation of EGFR, JNK, p38 MAPK, STAT1 and STAT3. 64 The findings of epigenetic silencing of SYK's expression and introduction of a senescence phenotype after induced demethylation in subsets of melanoma cell lines suggest that SYK is implicated in establishing and/or maintaining OIS, acting as an oncosuppressor agent. 65 More specifically, p53 as well as p53-dependent p21's activation by SYK repress the phosphorylation of pRB, altogether resulting in tumor growth inhibition.…”

“…From the perspective of oncogenesis, SYK's function has been a matter of investigation lately. It is shown that suppression of SYK increases EGFR‐derived signalling in mammary epithelial cells 63 and phosphorylation of EGFR, JNK, p38 MAPK, STAT1 and STAT3 64 . The findings of epigenetic silencing of SYK's expression and introduction of a senescence phenotype after induced demethylation in subsets of melanoma cell lines suggest that SYK is implicated in establishing and/or maintaining OIS, acting as an oncosuppressor agent 65 .…”

PARPs, PAR and NAD Metabolism and Their Inhibitors in Cancer

“…Interestingly, depletion of NMNAT1, which is involved in the synthesis of NAD+, PARP's substrate, induced DNA damage and sensitized cells to cisplatin but exhibited redundancy with PARPi in this respect [12]. Inhibition of EGFR or Syk (which mediates EGFR signaling) was synergistically cytotoxic in combination with olaparib in squamous cell carcinoma cells suggesting therapeutic potential [13].…”