Small molecular reverses chemoresistance of breast cancer through inhibition of DNA damage response

Targeting of DNA is a common and effective stratagem for cancer therapy, often seen in radiotherapy and DNA-damaging chemotherapy where lethal damage in DNA is inflicted upon treated cells. However, chemotherapy is often undermined by resistance in cancer cells. Because this issue remains unresolved, identifying ways to increase chemosensitivity in cancers is of critical importance. DNA-damaging chemotherapy treated cells activate the DNA damage response (DDR), which couples with activation of DNA repair processes. These processes are initiated and conducted by ATM/ATR sensor kinases which phosphorylate their downstream effector kinases Chk1/Chk2, and are known to counteract therapeutic efficacy. In order to identify ways to increase chemosensitivity in cancers, we tested a series of synthetic compounds with structural modifications of fern plant-derived protoapigenone for their ability to alter DDR in MCF-7 cell line. Among them, compound AT738 was the most potent on inhibition of cisplatin- or doxorubicin-induced ATM, Chk1, and Chk2 phosphorylation, and was therefore chosen for further study. As a result of DDR inhibition, AT738 increased chemosensitivity in doxorubicin-resistant MCF7-KCR cell line, which displays higher DDR related gene expression in ABCB1 independent mechanisms. Together, our findings suggest AT738 as a novel agent that, when used in combination with chemotherapy, can reverse multidrug resistance through inhibition of DDR.