Proteomics

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Regulation of CHK1 inhibitor resistance by a c-Rel and USP1 dependent pathway C4PR_LIV


ABSTRACT: The ATR-CHK1 signalling pathway responds to single strand DNA breaks and is required for cancer cells to survive the high levels of DNA replication stress and genomic instability resulting from the activity of oncogenes such as MYC. For this reason, inhibitors of CHK1 have great potential as anti-cancer drugs and are currently in clinical trials. However, overcoming de novo or acquired resistance to CHK1 inhibition is required if these are to be used as effective therapies. We discovered that lymphomas from the E-Myc mouse model of MYC driven B-cell lymphoma, with a deletion of the c-Rel NF-B subunit, have defective CHK1 activity and are resistant to treatment with the highly specific CHK1i CCT244747. Here we use quantitative (phospho)proteomics approaches to investigate how de novo resistance to CHK1i is acquired and can be overcome, offering potential therapeutic opportunity in patients developing resistance to Chk1i in the clinic.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Spleen

SUBMITTER: Amy Campbell  

LAB HEAD: Professor Claire E Eyers

PROVIDER: PXD026203 | Pride | 2022-10-19

REPOSITORIES: Pride

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Previously, we discovered that deletion of c-Rel in the Eµ-Myc mouse model of lymphoma results in earlier onset of disease, a finding that contrasted with the expected function of this NF-κB subunit in B-cell malignancies. Here we report that Eµ-Myc/cRel-/- cells have an unexpected and major defect in the CHK1 pathway. Total and phospho proteomic analysis revealed that Eµ-Myc/cRel-/- lymphomas highly resemble wild-type (WT) Eµ-Myc lymphomas treated with an acute dose of the CHK1 inhibitor (CHK1i  ...[more]

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