Mismatch repair (MMR)–deficient tumors exhibit proteome-wide protein instability and aggregation.

  • Major Finding: Mismatch repair (MMR)–deficient tumors exhibit proteome-wide protein instability and aggregation.

  • Concept: Preventing protein clearance using the neddylation blocker pevonedistat enhanced anti–PD-1 response.

  • Impact: This reveals a target in the large subset of MMR-deficient tumors that are immunotherapy resistant.

Tumors deficient in DNA mismatch repair (MMR) are often insensitive to chemotherapy, and although immune-checkpoint blockade (ICB) was recently approved for the treatment of microsatellite instability (MSI)–high tumors regardless of their cell type of origin, even immunotherapy is not always effective in these cases. Looking for other targetable vulnerabilities in MMR-deficient cancers, McGrail, Garnett, and colleagues used an algorithm they had previously developed to dredge gene-expression data from colorectal and endometrial cancers with MSI for hints about potentially effective therapeutics. This analysis pinpointed the selective Nedd8-Activating Enzyme 1 (NAE) inhibitor MLN4924 (pevonedistat), which showed evidence of efficacy in 2-D and 3-D in vitro experiments using colorectal cancer cells with MSI and in vivo xenograft experiments using tumors with MSI. Mechanistically, the mutations caused by MMR deficiency appeared to create destabilized proteins that were prone to misfolding and aggregation, and neddylation was required to clear these proteins and aggregates from cells, providing a possible explanation for the activity of pevonedistat in MSI-high tumors. Indeed, whole-proteome thermal stability was diminished in MSI-high cancer cell lines, patient-derived xenografts, and primary endometrial cancer samples, and increased proteome stability induced by increased protein chaperone expression reduced pevonedistat sensitivity. The accumulation of misfolded proteins in pevonedistat-treated MSI-high tumor cells implied that pevonedistat treatment may trigger the unfolded-protein response and, thus, cause immunogenic cell death, a hypothesis validated in further in vitro and in vivo experiments. This finding led to the idea that pevonedistat could potentiate ICB, a notion supported by the finding that anti–PD-1 plus pevonedistat was effective in treating mice with MSI-high endometrial tumors that did not respond to either agent alone. Together, these results identify proteome-wide protein instability as a targetable vulnerability in MSI-high tumors that are resistant to ICB and put forth pevonedistat as a candidate agent for further investigation.

McGrail DJ, Garnett J, Yin J, Dai H, Shih DJH, Lam TNA, et al. Proteome instability is a therapeutic vulnerability in mismatch repair-deficient cancer. Cancer Cell 2020 Feb 27 [Epub ahead of print].

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