UC San Diego

One major problem plaguing the medical community is patient relapse of cancer following targeted drug therapy. In a majority of patients with non-small-cell lung carcinoma, this process was shown to occur in as little as one year following treatment. Here we investigate the role that molecules, such as antioxidants, and cellular processes, such as DNA death, damage, and response, have in the underlying mechanistic basis for acquiring drug resistance. Our findings suggest that antioxidants are not capable of adequately preventing the acquisition of drug resistance, pointing toward R.O.S.-independent mechanisms of acquisition of drug resistance mutations. Additionally, we show that while the inhibition of DNA damage response and repair pathways significantly prevent the outgrowth of cancerous cells in the presence of drug, there is no difference in response from drug naïve versus drug-tolerant cancer cells. From these findings, we conclude that despite their reported disabled DNA repair machinery, drug-tolerant persister cells are not sensitized to death via inhibition of DNA damage response genes. Additionally, we elucidate the mechanism through which Disulfiram, a drug clinically approved for alcoholism which was recently reported to kill persister cells, induces persister cell-specific lethality. We find that Disulfiram does not kill persister cells through ALDH inhibition, as previously reported, but rather through an oxidative-apoptotic mechanism. By furthering the understanding of factors involved in the tumor’s acquisition of drug resistance, we provide insight into potential mechanisms to target through the development of new treatments aimed at preventing the occurrence of cancer relapses.