Brca2 deficiency drives gastrointestinal tumor formation and is selectively inhibited by mitomycin C

Chen, Xiaomin; Peng, Fangfei; Ji, Yan; Xiang, Hua; Wang, Xiang; Liu, Tingting; Wang, Heng; Han, Yumin; Wang, Changxu; Zhang, Yongfeng; Kong, Xiangyin; Lang, Jing-Yu

doi:10.1038/s41419-020-03013-8

“…The majority of GI cancers relapse within five years of surgical resection. In 2019, the 5-year overall survival rate after gastric cancer in China was approximately 20% [ 3 ], whereas that of colorectal cancer was 60% [ 4 ]. Consequently, accurate markers for therapy response are required to improve the prognosis of GI cancer patients [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Expression of Four Autophagy-Related Genes Accurately Predicts the Prognosis of Gastrointestinal Cancer in Asian Patients

Tang

¹

,

Liang

²

,

Xu

³

et al. 2021

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Gastrointestinal (GI) cancers are among the most fatal diseases in the world. Numerous studies have demonstrated the relationship between autophagy and development of gastrointestinal cancers. However, whether autophagy-related genes can predict prognosis of GI cancers in individuals of Asian ancestry has not been defined. This study, evaluated the prognostic value of autophagy-related genes in gastrointestinal cancer. Expression profile of autophagy-related genes for 296 gastrointestinal cancer patients of Asian ancestry was downloaded from the TCGA database (TCGA-LIHC, TCGA-STAD, TCGA-ESCA, TCGA-PAAD, TCGA-COAD, TCGA-CHOL, and TCGA-READ). The prognostic value of the autophagy-related genes was evaluated using univariate Cox, LASSO, and multivariate Cox regression analyses. The risk score of the autophagy-related gene signature was calculated to assess its predictive prognostic value for GI cancers. Forty-seven differentially expressed autophagy-related genes, in Asian patients with gastrointestinal cancers, were identified. Of the 47 genes, 4 were associated with prognosis of GI cancer (SQSTM1, BIRC5, NRG3, and CXCR4). A prognostic model for GI cancer, based on the expression of the above 4 genes in the training set, showed that cancer patients were stratified into high-risk and low-risk groups ( P < 0.05 ). The utility of the model for overall survival (OS) of GI cancer patients was consistent across the entire set, training set, and test set (entire set: P = 4.568 × 10 − 4 ; train set: P = 5.718 × 10 − 3 ; test set: P = 3.516 × 10 − 2 ). The sensitivity and specificity of the ROC curve of the above prognostic model in predicting the 5-year prognosis of GI cancer was satisfactory (entire set: 0.728; train set: 0.727; test set: 0.733). Analysis of clinical samples validated the overexpression of the 4 genes (SQSTM1, BIRC5, NRG3, and CXCR4) in tumor tissues relative to paired normal tissues, consistent with bioinformatic findings. Expression of the 4 autophagy-related genes (SQSTM1, BIRC5, NRG3, and CXCR4) can accurately predict the prognosis of gastrointestinal tumors in Asian patients.

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“…After treatment with MMC, CA19-9 levels were markedly reduced to normal levels after 3 years and the patient remained asymptomatic, suggesting a potential therapeutic effect of MMC for individuals with PC with genomic changes consistent with DNA repair abnormalities [ 13 ]. Murine models of gastrointestinal malignances with BRCA mutations were also consistent with these findings, indicating that MMC could be an option for gastrointestinal tumors with BRCA deficiency [ 20 ].…”

Section: Introductionmentioning

confidence: 59%

“…HRD tumors are more responsive to platinum-based chemotherapy due to impaired DNA repair pathways [ 22 , 23 ]. Furthermore, these tumors demonstrate fragility to exposure to PARPis, with a synthetically lethal interaction due to accumulation of double-strand DNA breaks [ 13 , 20 ]. Nowadays, olaparib, a PARPi, is FDA approved for maintenance treatment of patients with deleterious germline BRCA -mutated metastatic PC, with controlled disease for at least 16 weeks of a first-line platinum-based chemotherapy regimen.…”

Section: Discussionmentioning

confidence: 99%

Mitomycin C in Homologous Recombination Deficient Metastatic Pancreatic Cancer after Disease Progression on Platinum-Based Chemotherapy and Olaparib

Botrus

¹

,

Roe

²

,

Jameson

³

et al. 2022

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Recent efforts to personalize treatment with platinum-based chemotherapy and PARP inhibitors have produced promising results in homologous recombinant deficient (HRD) metastatic pancreatic cancer (MPC). However, new strategies are necessary to overcome resistance. The below case series documents patients treated at the HonorHealth Research Institute with a diagnosis of HRD MPC who received Mitomycin C (MMC) treatment from January 2013 until July 2018. Five HRD MPC patients treated with MMC were evaluated. All patients received at least one course of treatment. Mean age at MMC treatment initiation was 58 years. There were 3 females and 2 males. All patients had tumors that progressed on platinum-based chemotherapy, four patients had previous exposure to Olaparib. The median PFS was 10.1 months, and the median OS was 12.3 months. Responses were observed only in patients harboring BRCA2 mutations, no response was observed in the PALB2 mutation carrier. MMC in this heavily previously treated PC was safe, with overall manageable grade 2 gastrointestinal toxicities including nausea and vomiting, and G3 hematological toxicities including anemia and thrombocytopenia. Pancreatic cancer patients with HRD may benefit from MMC treatment. Further clinical investigation of MMC in pancreatic cancer is warranted.

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“…Lentiviruses containing human CRISPR Knockout Pooled Library (Brunello) (a gift from David Root and John Doench, Addgene#73179) were produced by HEK293T cells and were precipitated by PEG buffer as previously reported (Liu et al , 2019; Chen et al , 2020b). 5 × 10 8 Capan‐1/TP cells were infected with virus‐containing library sgRNA at an MOI of 0.4.…”

Section: Methodsmentioning

confidence: 99%

Thioparib inhibits homologous recombination repair, activates the type I IFN response, and overcomes olaparib resistance

Wang

¹

,

Wang

²

,

Chen

³

et al. 2023

Self Cite

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Poly‐ADP‐ribose polymerase (PARP) inhibitors (PARPi) have shown great promise for treating BRCA‐deficient tumors. However, over 40% of BRCA‐deficient patients fail to respond to PARPi. Here, we report that thioparib, a next‐generation PARPi with high affinity against multiple PARPs, including PARP1, PARP2, and PARP7, displays high antitumor activities against PARPi‐sensitive and ‐resistant cells with homologous recombination (HR) deficiency both in vitro and in vivo. Thioparib treatment elicited PARP1‐dependent DNA damage and replication stress, causing S‐phase arrest and apoptosis. Conversely, thioparib strongly inhibited HR‐mediated DNA repair while increasing RAD51 foci formation. Notably, the on‐target inhibition of PARP7 by thioparib‐activated STING/TBK1‐dependent phosphorylation of STAT1, triggered a strong induction of type I interferons (IFNs), and resulted in tumor growth retardation in an immunocompetent mouse model. However, the inhibitory effect of thioparib on tumor growth was more pronounced in PARP1 knockout mice, suggesting that a specific PARP7 inhibitor, rather than a pan inhibitor such as thioparib, would be more relevant for clinical applications. Finally, genome‐scale CRISPR screening identified PARP1 and MCRS1 as genes capable of modulating thioparib sensitivity. Taken together, thioparib, a next‐generation PARPi acting on both DNA damage response and antitumor immunity, serves as a therapeutic potential for treating hyperactive HR tumors, including those resistant to earlier‐generation PARPi.

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Brca2 deficiency drives gastrointestinal tumor formation and is selectively inhibited by mitomycin C

Cited by 6 publications

References 67 publications

Expression of Four Autophagy-Related Genes Accurately Predicts the Prognosis of Gastrointestinal Cancer in Asian Patients

Expression of Four Autophagy-Related Genes Accurately Predicts the Prognosis of Gastrointestinal Cancer in Asian Patients

Mitomycin C in Homologous Recombination Deficient Metastatic Pancreatic Cancer after Disease Progression on Platinum-Based Chemotherapy and Olaparib

Thioparib inhibits homologous recombination repair, activates the type I IFN response, and overcomes olaparib resistance

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