In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. NG14-NG14
Abstract:
Deficient DNA mismatch repair (dMMR) induces a hypermutator phenotype, leaving a genomic scar known as microsatellite instability (MSI). MSI is observed in approximately 30% of endometrial cancers, 20% of gastric cancers, 15% of colorectal cancers, and in a smaller fraction of other tumor types. This hypermutator phenotype is thought to produce large numbers of immunogenic neoantigens, leading to the approval of MSI status as a clinical biomarker for immunotherapy. However, more than 60% of patients with MSI tumors fail to respond to immune checkpoint therapy. To uncover alternative therapeutic vulnerabilities for these patients, we used transcriptome signature-guided approaches to identify MLN4924 (pevonedistat), a Nedd8-activating enzyme inhibitor, as a potential therapy for dMMR/MSI cancers. We discover that destabilizing mutations from the dMMR mutation process lead to rampant proteome instability in MSI tumors, resulting in an abundance of misfolded protein aggregates. To compensate, MSI cancer cells activate a Nedd8-mediated degradation pathway to facilitate clearance of misfolded proteins, which is blocked by treatment with MLN4924. The accumulation of misfolded proteins in MSI cancer cells following MLN4924 treatment activated the unfolded protein response, promoted immune cell migration, and induced immunogenic cell death. Antitumor vaccination with MLN4924-treated cells stimulated the generation of endogenous tumor antibodies and prevented tumor incidence upon re-challenge. Based on this immunostimulation, we combined MLN4924 with PD1 blockade, finding that the combination increased recruitment of CD8+ lymphocytes and improved therapeutic efficacy beyond either treatment alone. Taken together, our results indicate that targeting proteome instability is a novel therapeutic avenue for MSI patients and may potentiate immune checkpoint blockade, potentially increasing the depth and duration of response, as well as the fraction of dMMR/MSI patients who can benefit. Citation Format: Nidhi Sahni, Daniel J. McGrail, Jeannine Garnett, Jun Yin, Hui Dai, David J. H. Shih, Guang Peng, David Menter, Melinda S. Yates, Scott Kopetz, Karen Lu, Russell Broaddus, Gordon B. Mills, Shiaw Y. Lin. Proteome instability is an immunogenic therapeutic vulnerability in mismatch repair deficient cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr NG14.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2020-NG14
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2020
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
