Exploiting immune surveillance to target colorectal cancer
Alberto Bardelli
University of Turin and IFOM ETS – The AIRC Institute of Molecular Oncology, Milan
The emergence of drug resistance limits the efficacy of targeted therapies in human tumors. Strategies to prevent or overcome resistance are essential to design the next generation of clinical trials. The prevalent view is that resistance is a fait accompli: when treatment is initiated, cancers already contain drug-resistant mutant cells. Notably, bacteria exposed to antibiotics transiently increase their mutation rates (adaptive mutability) thus improving chances of survival. We studied colorectal cancer (CRC) to assess whether tumour cells similarly exploit adaptive mutability to evade therapeutic pressure. We found that EGFR and BRAF inhibition activates stress-induced mutagenesis through downregulation of MMR and HR DNA repair effectors, and concomitant up-regulation of error-prone polymerases in drug-tolerant persister cells resulting in increased mutation rates. Overcoming drug resistance, therefore, means considering as a target not “only” individual oncogenes but also the evolving nature of human tumors. One possibility is to unleash the ability of the immune system to recognize mutations induced by therapy. We tested this possibility in syngeneic mouse models of CRC. Our findings indicate that inactivation of DNA repair mechanisms and manipulation of mutational loads can trigger immune surveillance and prolonged therapeutic responses.