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Regorafenib and Nivolumab in Mismatch Repair (MMR) Refractory Colorectal Cancer

ABSTRACT: The main purpose of this study is to test the safety, tolerable side effects, and determine the highest tolerable dose of the combination of Regorafenib and Nivolumab. Researchers want to find out if this combination of Regorafenib and Nivolumab can help people with metastatic colorectal cancer with mismatch repair (MMR) proficiency.

DISEASE(S): Metastatic Colorectal Cancer,Colon Cancer,Colorectal Cancer,Colorectal Neoplasms,Colonic Neoplasms

PROVIDER: 2287352 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:DNA mismatch repair (MMR) is an evolutionarily conserved process that corrects innate DNA polymerase infidelities during replication to maintain genomic integrity. Defects in a subset of MMR genes are associated with hereditary non-polyposis colon cancer and some other sporadic cancers, highlighting the crucial role for MMR in genome maintenance. In E. coli a helicase implicated in the MMR process is well characterized, and named UvrD, whereas in mammals it has not been identified yet, even though the eukaryotic DNA mismatch pathway is analogous to the bacterial one and uses a similar repair mechanism and key components. Here we identify MCM9 as a helicase playing a vital role in MMR in mammals. MCM9 is the last discovered member of the MCM2-9 family, and has been implicated in replication and homologous recombination processes. By an affinity-purification proteomic approach, we found that MCM9 interacts with the MMR initiation complex. Immortalized cells from MCM9 knockout mice showed clear length alterations in their microsatellites, and a dramatic MMR deficiency compared to wild-type cells. We also found that a helicase-dead form of MCM9 is totally unable to restore the MMR deficiency phenotype. Furthermore, using an siRNA approach in human cells, we demonstrated that MCM9 is regulated by MSH2, a protein responsible for mismatch recognition. Our results clearly reveal that MCM9 functions as a helicase for DNA mismatch repair in mammals, and thus is essential for the maintenance of genome stability. Proteomics analysis: FLAG-HA-tagged human MCM9 plus associated proteins were isolated by tandem affinity purification from nuclear extracts of stably-expressing HeLa S3 cells, then analysed by SDS-PAGE and silver staining. Gel lanes were cut into slices, which were processed and analysed separately. Proteins in each gel slice were digested with trypsin, extracted and analysed by LC-MS/MS on a Thermo Scientific LTQ Velos mass spectrometer, generating a series of MS RAW files. Bioinformatics: Peptide and protein identification from MS data was performed using the Sequest program, with a human IPI sequence database (v.3.60). Trypsin was defined as the protease used, a peptide mass tolerance of 2.5 was specified, and all peptide matches have a Sequest Xcorr score ≥0.5.

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Regorafenib and Nivolumab in Mismatch Repair (MMR) Refractory Colorectal Cancer

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