SHP2-mediated inhibition of DNA repair contributes to cGAS-STING activation and chemotherapeutic sensitivity in colon cancer

PURPOSE Carmustine (BCNU) resistance has been correlated with tumor expression of the DNA repair enzyme O6-alkylguanine-DNA alkyltransferase (AT). It has been shown that streptozotocin will deplete AT activity of human colon cancer cells in vitro and potentiate BCNU cytotoxicity. This clinical trial was conducted to determine whether streptozotocin can be used as a modulator of AT in metastatic colorectal cancers and thereby overcome clinical resistance to BCNU. PATIENTS AND METHODS Fifteen patients with fluorouracil-resistant metastatic colon or rectal cancers were treated sequentially with 2 g/m2 of streptozotocin followed 5 1/2 hours later by BCNU. Sequential biopsies of metastases before and after streptozotocin were conducted to determine whether streptozotocin depletes tumor AT. Peripheral-blood mononuclear cells (PBMCs) were evaluated as a surrogate tissue for prediction of baseline AT levels and streptozotocin posttreatment modulation of the AT in metastases. RESULTS Streptozotocin treatment led to a 78% (range, 69% to 89%) decrease in the AT levels in colon cancer metastases; however, myelosuppression and hepatic toxicity limited the BCNU dose to 130 mg/m2. A similar decrease in AT levels of PBMCs was found; however, the absolute levels of AT in PBMCs at baseline and following streptozotocin were not predictive of the levels expressed in metastases from the same patient. Despite the decrease in tumor levels of AT, no clinical responses were observed. CONCLUSION Streptozotocin decreases but does not fully deplete AT activity in metastatic colorectal cancers and the residual AT level in metastases is sufficient to maintain clinical resistance to BCNU. We have also demonstrated that sequential computed tomography (CT)-directed biopsies of colorectal cancer metastases can be used to evaluate strategies to investigate modulators of AT-directed repair. AT levels of PBMCs do not predict for the AT level or degree of modulation achieved in the metastatic tumor.

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Repressing DNA Repair to Enhance Chemotherapy: Targeting MyD88 in Colon Cancer

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/djt148 ◽

2013 ◽

Vol 105 (13) ◽

pp. 926-927 ◽

Cited By ~ 5

Author(s):

E. A. Williamson ◽

R. Hromas

Keyword(s):

Colon Cancer ◽

Dna Repair

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Molecular Portrait of Metastasis-Competent Circulating Tumor Cells in Colon Cancer Reveals the Crucial Role of Genes Regulating Energy Metabolism and DNA Repair

Clinical Chemistry ◽

10.1373/clinchem.2016.263582 ◽

2017 ◽

Vol 63 (3) ◽

pp. 700-713 ◽

Cited By ~ 34

Author(s):

Catherine Alix-Panabières ◽

Laure Cayrefourcq ◽

Thibault Mazard ◽

Thierry Maudelonde ◽

Eric Assenat ◽

...

Keyword(s):

Colon Cancer ◽

Dna Repair ◽

Stem Cell ◽

Energy Metabolism ◽

Tumor Cells ◽

Complementation Group ◽

Peroxisome Proliferator ◽

Metastasis Formation ◽

Peroxisome Proliferator Activated Receptor ◽

Tumor Relapse

AbstractBACKGROUNDUnraveling the molecular mechanisms that regulate the biology of metastasis-competent circulating tumor cells (CTCs) is urgently needed to understand metastasis formation and tumor relapse. Our group previously established the first cell line (CTC-MCC-41) derived from metastasis-competent CTCs of a patient with colon cancer.METHODSIn this study, we analyzed the transcriptome of CTC-MCC-41 cells using Human Genome U133 Plus 2.0 microarrays with the aim of unraveling the molecular basis of their special features (stem cell properties and ability to initiate and support metastasis formation).RESULTSComparison of the transcriptome data of metastasis-competent CTC-MCC-41 cells and of HT-29 cells (derived from a primary colon cancer) highlights the differential expression of genes that regulate energy metabolism [peroxisome proliferator-activated receptor γ coactivator 1A (PPARGC1A), peroxisome proliferator-activated receptor γ coactivator 1B (PPARGC1B), fatty acid binding protein 1 (FABP1), aldehyde dehydrogenase 3 family member A1 (ALDH3A1)], DNA repair [BRCA1 interacting protein C-terminal helicase 1 (BRIP1), Fanconi anemia complementation group B (FANCB), Fanconi anemia complementation group M (FANCM)], and stemness [glutaminase 2 (GLS2), cystathionine-beta-synthase (CBS), and cystathionine gamma-lyase (CTH)]. The differential expression of 20 genes was validated by quantitative reverse transcription PCR.CONCLUSIONSThis study gives a comprehensive outlook on the molecular events involved in colon cancer progression and provides potential CTC biomarkers that may help develop new therapies to specifically target CTCs with stem cell properties that cause metastases and tumor relapse in patients with colon cancer.

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