Leveraging the DNA damage response impairs the emergence of resistance to targeted therapies in colorectal cancer cell lines

The advent of molecularly targeted therapies has transformed the treatment of cancer patients, but the almost inevitable emergence of secondary resistance significantly hampers their clinical efficacy. We and others previously showed that targeted therapies, while not being directly genotoxic, increase DNA damage in treated cells and promote mutagenic DNA replication. We hypothesized that inhibiting DNA damage response (DDR) systems with inhibitors (DDRi) currently under clinical development could increase treatment-induced DNA damage to cytotoxic levels, thus interfering with the emergence of genetic resistance. Using colorectal cancer cell lines as model system, we found that combinatorial treatment with DDRi increased cells sensitivity to standard-of-care targeted therapies and reduced the abundance of surviving (‘persister’) cells. DDR inhibition significantly increased DNA damage induced by standard targeted therapies by increasing DNA replication fork instability. Of translational relevance, combination with DDRi significantly delayed or even abolished the emergence of resistance to targeted therapies in in vitro time-to-progression assays. Our results show that DNA damage induced by targeted therapies represents a previously underappreciated vulnerability of cancer cells, and that combined treatment with DDRi could represent a promising therapeutic approach to delay or even prevent the emergence of drug resistance.