Targeting Topoisomerase I and DNA with LCS1269 Drives Glioblastoma Cell Death Despite ATM/Chk1/BRCA1/RAD51 Signaling Pathway Activation.

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. The success of modern multimodal standards approved in anti-glioblastoma therapy remains limited. Consequently, new therapeutics are urgently needed. In this study, utilizing ex vivo, in silico, and in vitro approaches, we investigated the LCS1269 effects on two potential targets, DNA and Top I. We also elucidated the influence of LCS1269 on signaling pathways and GBM cell viability. Based on our docking data and competition studies results, we demonstrated that LCS1269 may bind to DNA, demonstrating selectivity toward AT-rich regions. We also showed that LCS1269 could dock both Top I/DNA binary complex and Top I active sites. LCS1269 caused Top I dysfunction and downregulated the expression of Top I. Moreover, the LCS1269 treatment of GBM cells facilitated DNA damage and the activation of the ATM/Chk1/BRCA1/Rad51 pathway. Meanwhile, DNA damage response induction and ATM/Chk1/BRCA1/Rad51 pathway activation were insufficient to prevent GBM cell death triggered by LCS1269 treatment. Our work shows that DNA and Top I are promising molecular targets of LCS1269, thus providing insight on several novel mechanisms of its anti-tumor activity. Nonetheless, we did not perform a biophysical validation of the LCS1269-DNA interaction, which is a limitation of our study.