Abstract
Cancer treatment has been revolutionised by targeted therapies which act by blocking the pathways that drive cancer. However, the effects of targeted therapies are invariably short-lived and relapse is inevitable. Recent studies have revealed that “drug-tolerant persisters” (DTPs); a subpopulation of cells, play a crucial role in tumour recurrence and treatment failure. DTPs possess the unique ability to survive and persist in the presence of high drug concentrations by entering a dormant state. Interestingly, DTPs share similar characteristics to cancer stem cells (CSCs).
Research has shown that the treatment of lung adenocarcinoma cells with an EGFR (Epidermal Growth Factor Receptor) inhibitor, triggered cell signalling pathways that led to a switch of cancer cells to a stem-cell-like state and increased tumour initiation capacity. A comparable scenario has been observed in apoptotic cancer cells. Studies have elucidated that apoptotic tumour cells release growth-stimulating signals to encourage tumour re-population. Proteases (caspase 3 & 7) as well as prostaglandin E2 (PGE2), have been identified as key players in this process. Despite induced cell death by targeted therapy, the production of PGE2 results in the repopulation of nearby CSCs. Therefore, considering the similarities between CSCs and DTPs, it is hypothesised that paracrine signalling from apoptotic cells promotes the emergence of DTPs.
To explore the effect of apoptotic cells on the emergence of DTPs, proliferation assays were conducted on PC9 and H358 cell lines. PC9 cells were treated with osimertinib alone or in combination with indomethacin; a COX inhibitor that blocks prostaglandin signalling. Similarly, H358 cells were treated with sotorasib alone or in combination with indomethacin. In addition, expression of the stemness genes NANOG and OCT3/4 and surfactant genes (SFTPB, SFTPC, SFTPD) was also investigated in PC9 and H358 cell lines upon treatment with indomethacin alone or in combination with targeted therapy using RT-qPCR.
The results revealed that while indomethacin, in combination with osimertinib/sotorasib, led to a reduction in cancer cell growth (PC9/H358), the effect of combination treatment was not significantly different from that of treatment with osimertinib/sotorasib alone suggesting that indomethacin had no affect cell proliferation. Further, RT-qPCR results revealed downregulation of NANOG and SFTPB gene expression in H358 cells with combinational treatment compared to sotorasib treatment alone.
Thus, further studies are needed to confirm whether blocking paracrine signalling has a significant effect on the emergence of DTPs and whether it improves the efficacy of targeted therapy. Confirmation studies can be carried out using other prostaglandin inhibitors such as celecoxib & aspirin in combination with targeted therapy.