BRCA1 and BRCA2 mutations sensitize to chemotherapy in patient-derived pancreatic cancer xenografts

Lohse, Ines; Borgida, Ayelet; Cao, Pinjiang; Cheung, Melissa; Pintilie, Melania; Bianco, Teresa; Holter, Spring; Ibrahimov, Emin; Kumareswaran, Ramanan; Bristow, Robert G.; Tsao, Ming‐Sound; Gallinger, Steven; Hedley, David W.

doi:10.1038/bjc.2015.220

Cited by 70 publications

(59 citation statements)

References 25 publications

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“…The third model, OCIP28, is derived from a patient with a germline BRCA2 mutation and is highly sensitive to gemcitabine as previously reported. 26 There was a modest, non-significant reduction in the growth of this model treated with MK-1775 alone, which might be linked to a recently-suggested role for Wee1 in homologous repair, 6,13 but similar to the other 2 models, and in contrast to an earlier paper, 15 we did not see strong evidence for a synergistic interaction between the 2 drugs. Treatments were well tolerated in the mice, with no significant loss of body weight (Fig.…”

Section: Effects Of Mk-1775 In Combination With Gemcitabinecontrasting

confidence: 56%

Cytokinetic effects of Wee1 disruption in pancreatic cancer

et al. 2016

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The Wee1 kinase, which is activated in response to DNA damage, regulates exit from G2 through inhibitory phosphorylation of Cdk1/Cdc2, and is an attractive drug target. However, recent work has highlighted effects of Cdk2 phosphorylation by Wee1 on movement through S-phase, suggesting the potential to sensitize to S-phase specific agents by Wee1 inhibitors. In this paper we applied multiparametric flow cytometry to patient-derived pancreatic cancer xenograft tumor cells to study the cell cycle perturbations of Wee1 disruption via the small molecule inhibitor MK-1775, and genetic knockdown. We find that in vitro treatment with MK-1775, and to a lesser degree, Wee1 RNA transcript knockdown, results in the striking appearance of S-phase cells prematurely entering into mitosis. This effect was not seen in vivo in any of the models tested. Here, although we noted an increase of S-phase cells expressing the damage response marker gH2AX, treatment with MK-1775 did not significantly sensitize cells to the cytidine analog gemcitabine. Treatment with MK-1775 did result in a transient but large increase in cells expressing the mitotic marker phosphorylated H3S10 that reached a peak 4 hours after treatment. This suggests a role for Wee1 regulating the progression of genomically unstable cancer cells through G2 in the absence of extrinsically-applied DNA damage. A single dose of 8Gy ionizing radiation resulted in the time-dependent accumulation of Cyclin A2 positive/phosphorylated H3S10 negative cells at the 4N position, which was abrogated by treatment with MK-1775. Consistent with these findings, a genomescale pooled RNA interference screen revealed that toxic doses of MK-1775 are suppressed by CDK2 or Cyclin A2 knockdown. These findings support G2 exit as the more significant effect of Wee1 inhibition in pancreatic cancers.

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Section: Effects Of Mk-1775 In Combination With Gemcitabinecontrasting

confidence: 56%

Cytokinetic effects of Wee1 disruption in pancreatic cancer

et al. 2016

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“…Lohse et al (24) identified that BRCA1 and BRCA2 mutant xenografts were significantly more sensitive to cisplatin compared with the control, while the BRCA1 and BRCA2 wild type models exhibited sensitivity to gemcitabine but not to cisplatin. However, BRCA1 expression was significantly decreased in the HCT-8 cells compared with in the drug-resistant cells.…”

Section: Discussionmentioning

confidence: 99%

BRCA1 expression serves a role in vincristine resistance in colon cancer cells

Zhang

2017

Oncology Letters

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Abstract. The present study aimed to investigate the association between breast cancer susceptibility gene 1 (BRCA1) expression and drug resistance in colon cancer, with the specific aim of elucidating the underlying molecular mechanisms of vincristine (VCR) resistance in tumor cells. The HCT-8 human colon cancer cell line was used to establish the VCR-resistant HCT-8/V line by gradually increasing the concentration of VCR during cell culture. The relative mRNA and protein expression levels of BRCA1 in these colon cancer cell lines was assessed by reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) analysis and western blotting, respectively. Resistance to VCR was established in the HCT-8/V colon cancer cells, and RT-qPCR and western blot analysis revealed the expression of BRCA1 to be significantly higher in the VCR-resistant cells compared with their drug-sensitive counterparts (P<0.05). The decreased BRCA1 expression in these VCR-resistant cells may be associated with the drug resistance frequently observed in colon cancer. IntroductionColon cancer is one of the most common malignant tumors of the digestive system. With economic development and changes in lifestyle, the incidence of colon cancer is increasing, endangering human life and health (1). Chemotherapy is an important treatment strategy for colon cancer (2); however, it is a long process involving drug combinations and the administration of large doses of drugs. Tumor drug resistance has become increasingly frequent and is a problem for the treatment of colon cancer and other malignant tumors (3). Notably, 90% of cancer mortalities are associated with tumor drug resistance (4), therefore the underlying molecular mechanisms regulating the development of drug resistance are a key focus of malignant tumor research. Mechanisms of drug resistance in tumors include the modification of drug targets, repair of damaged cells, and the activation or inhibition of cell death signaling pathways. These processes can result from gene mutations, deletions or amplifications, in addition to epigenetic changes that occur via abnormal DNA methylation or the post-transcriptional regulation of microRNAs (miRNAs) (5-7).Vincristine (VCR), the most frequently used chemotherapy drug in the clinical treatment of colon cancer, is a cell cycle-specific drug that binds to tubulin, thereby inhibiting the assembly of microtubule structures and arresting mitosis in metaphase (8). The tumor suppressor breast cancer susceptibility gene 1 (BRCA1) confers increased susceptibility to breast and ovarian cancers, and mutations in the BRCA1 gene are present in ≤50% of inherited breast cancers (9,10). In women <50 years old, the risk of colorectal cancer is increased in carriers of BRCA1 mutations (11).In the current study, the expression of BRCA1 was verified by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis and western blotting, to investigate the role of BRCA1 in modulating VCR resistance. The findings reported here demonstrate potential...

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“…Preclinical models using PDAC cell lines as well as patient-derived murine xenografts have shown that tumor BRCA2 deficiency was significantly associated with sensitivity to DNA cross-linking agents (such as platinum salts), as well as radiation therapy compared with BRCA2 proficiency (Porcelli et al 2013, Andrei et al 2015, Lohse et al 2015. In addition to case reports (Sonnenblick et al 2011), several retrospective case series have described marked efficacy of platinum salts in BRCA2 mutation carriers with advanced PDAC (Lowery et al 2011, Golan et al 2014, Luo et al 2015, Vyas et al 2015.…”

Section: Use Of Cross-linking Cytotoxic Agents In Brca2 Mutation Carrmentioning

confidence: 99%

Pancreatic ductal adenocarcinoma in BRCA2 mutation carriers

Mestier

Danset

Neuzillet

et al. 2016

Endocrine-Related Cancer

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Germline BRCA2 mutations are the first known cause of inherited (familial) pancreatic ductal adenocarcinoma (PDAC). This tumor is the third most frequent cancer in carriers of germline BRCA2 mutations, as it occurs in around 10% of BRCA2 families. PDAC is known as one of the most highly lethal cancers, mainly because of its chemoresistance and frequently late diagnosis. Based on recent developments in molecular biology, a subgroup of BRCA2-associated PDAC has been created, allowing screening, early surgical treatment and personalized systemic treatment. BRCA2 germline mutation carriers who have ≥1 first-degree relative, or ≥2 blood relatives with PDAC, should undergo screening and regular follow-up based on magnetic resonance imaging and endoscopic ultrasound. The goal of screening is to detect early invasive PDAC and advanced precancerous lesions suitable for a stepwise surgical complete (R0) resection. Increasing evidence on the molecular role of the BRCA2 protein in the homologous recombination of DNA damages suggest that BRCA2-related PDAC are sensitive to agents causing DNA cross-linking damage, such as platinum salts, and treatments targeting rescue DNA repair pathways, such as poly(ADP-ribose) polymerase inhibitors that are currently under investigation.

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BRCA1 and BRCA2 mutations sensitize to chemotherapy in patient-derived pancreatic cancer xenografts

Cited by 70 publications

References 25 publications

Cytokinetic effects of Wee1 disruption in pancreatic cancer

Cytokinetic effects of Wee1 disruption in pancreatic cancer

BRCA1 expression serves a role in vincristine resistance in colon cancer cells

Pancreatic ductal adenocarcinoma in BRCA2 mutation carriers

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