6533b7d8fe1ef96bd1269882

RESEARCH PRODUCT

In the literature: April 2020

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Deficient DNA mismatch repair (dMMR) may be caused by germline or somatic mutations in mismatch repair genes ( MLH1 , MSH2 , MSH3 , MSH6 and PMS2 ) or through epigenetic silencing of MLH1 .1 dMMR induces a hypermutator phenotype, also known as microsatellite instability (MSI). Next-generation sequencing identifies MSI in 12 cancer types. The highest prevalence is seen in endometrial cancer (31.4%), followed by colorectal cancer (19.7%) and gastric cancer (GC, 19.1%). MSI was related to better prognosis for colorectal cancer and GC . Moreover, the dMMR/MSI hypermutator phenotype is thought to produce large numbers of immunogenic neoantigens that can be recognised by immune cells, leading to the approval of MSI status as a predictive biomarker for checkpoint inhibitors, independently from tumour origin. Nevertheless, more than 60% of patients with MSI will eventually develop resistance to immunotherapy2 and many of them also exhibit intrinsic resistance to chemotherapeutics, making their treatment options very limited.3 In a recent article published in Cancer Cell , McGrail et al 4 sought to find alternative therapeutic vulnerabilities for dMMR/MSI cancers. This study shows that dMMR/MSI tumours exhibit whole-proteome instability associated with a large burden of destabilising mutations. In this scenario, the role of Nedd8-dependent clearance of misfolded proteins, which can be blocked with an Nedd8-activating enzyme (NAE) E1 inhibitor, was found to be relevant. On treatment, dMMR/MSI tumours accumulated misfolded proteins, which ultimately induced immunogenic synergic cell death when combined with a checkpoint inhibitor. In the MSI endometrial cancer model analysed in these experiments, anti-PD1 (programmed death receptor)) alone was insufficient to reduce tumour growth. However, when the combination of MLN4924, an NAE inhibitor, and checkpoint blockade inhibition was tested, it was possible to observe a more homogeneous response. Furthermore, numerous studies have linked high mutational burden with immunotherapy response across diverse tumours. …