Leveraging the DNA damage response impairs the emergence of resistance to targeted therapies in colorectal cancer
Molecularly targeted therapies have transformed the treatment of cancer patients, but the almost inevitable emergence of secondary resistance blunts their clinical efficacy. We and others previously showed that targeted therapies, while not being directly genotoxic, increase genomic instability and promote mutagenic DNA replication, a process which is integral to the acquisition of resistance to treatment. Using colorectal cancer cell lines and patient-derived models, we found that targeted treatment induced DNA double-strand breaks (DSBs), which were counteracted by activation of DSB repair mediated by the Wnt/ß-catenin pathway. Inhibitors of the DNA damage response (DDRi) activated downstream DSBs synergized with targeted therapies, and delayed or completely abolished the emergence of resistance to targeted treatment by eradicating surviving drug-tolerant 'persister' cells. Mechanistically, DDR blockade enhanced the DNA damage induced by targeted therapies and prevented cells from recovery. Of translational relevance, DDRi increased response to targeted treatment in patient-derived organoids, and the combination with WEE1 inhibitor adavosertib achieved stable tumor control and hindered the emergence of resistance to clinically approved targeted therapies in vivo. 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 restrict the emergence of drug resistance.
Molecularly targeted therapies have transformed the treatment of cancer patients, but the almost inevitable emergence of secondary resistance blunts their clinical efficacy. We and others previously showed that targeted therapies, while not being directly genotoxic, increase genomic instability and promote mutagenic DNA replication, a process which is integral to the acquisition of resistance to treatment. Using colorectal cancer cell lines and patient-derived models, we found that targeted treatment induced DNA double-strand breaks (DSBs), which were counteracted by activation of DSB repair mediated by the Wnt/ß-catenin pathway. Inhibitors of the DNA damage response (DDRi) activated downstream DSBs synergized with targeted therapies, and delayed or completely abolished the emergence of resistance to targeted treatment by eradicating surviving drug-tolerant 'persister' cells. Mechanistically, DDR blockade enhanced the DNA damage induced by targeted therapies and prevented cells from recovery. Of translational relevance, DDRi increased response to targeted treatment in patient-derived organoids, and the combination with WEE1 inhibitor adavosertib achieved stable tumor control and hindered the emergence of resistance to clinically approved targeted therapies in vivo. 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 restrict the emergence of drug resistance.