Therapeutic targeting of mismatch repair-deficient cancers

Abstract

DNA mismatch repair (MMR) is one of many evolutionarily conserved processes that act as guardians of genomic integrity. MMR proteins recognize errors that occur during DNA replication and initiate countermeasures to rectify those mistakes. MMR deficiency (MMRd) therefore leads to a dramatic accumulation of mutations. The MMRd genomic signature is characterized by a high frequency of single-base substitutions as well as insertions and/or deletions that preferentially occur in short nucleotide repeat sequences known as microsatellites. This accumulation leads to a phenomenon termed microsatellite instability, which accordingly serves as a marker of underlying MMRd. MMRd is associated with hereditary cancer syndromes such as Lynch syndrome and constitutional MMRd as well as with sporadic tumour development across a variety of tissues. High baseline immune cell infiltration is a characteristic feature of MMRd/microsatellite instability-high tumours, as is the upregulation of immune checkpoints. Importantly, the molecular profile of MMRd tumours confers remarkable sensitivity to immune-checkpoint inhibitors (ICIs). Many patients with MMRd disease derive durable clinical benefit when treated with these agents regardless of the primary tumour site. Nevertheless, a substantial subset of these patients will fail to respond to ICI, and increasing research is focused on identifying the factors that confer resistance. In this Review, we begin by discussing the biological function of the MMR machinery as well as the genomic sequelae of MMRd before then examining the clinical implications of MMRd with a specific focus on cancer predisposition, diagnostic approaches, therapeutic strategies and potential mechanisms of resistance to ICIs.