Treatment opportunities and future perspectives for pancreatic cancer patients with germline BRCA1-2 pathogenic variants

Macchini, Marina; Centonze, Federico; Peretti, Umberto; Orsi, Giulia; Militello, Anna Maria; Valente, Maria Giovanna; Cascinu, Stefano; Reni, Michele

doi:10.1016/j.ctrv.2021.102262

Cited by 20 publications

(11 citation statements)

References 90 publications

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“…Pancreatic adenocarcinoma (PAAD) is the most deadly malignant tumor of the digestive tract [ 1 ]. The incidence of PAAD increases year by year, and the 5-year survival rate is less than 5%.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, although chemotherapy is the main treatment used to shrink or reduce the growth of this cancer, allowing patients to live longer, it is not curing it. Drug resistance is also a huge obstacle in the improvement of the overall survival, and nearly 80% of PAAD patients undergoing surgical resection are at risk of recurrence [ 1 ]. However, 80% of PAAD patients eventually die from tumor metastasis regardless of whether they have undergone surgical resection or not.…”

Section: Introductionmentioning

confidence: 99%

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Curcumin Derivative C66 Suppresses Pancreatic Cancer Progression through the Inhibition of JNK-Mediated Inflammation

et al. 2022

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Pancreatic adenocarcinoma is by far the deadliest type of cancer. Inflammation is one of the important risk factors in tumor development. However, it is not yet clear whether deterioration in pancreatic cancer patients is related to inflammation, as well as the underlying mechanism. In addition, JNK is abnormally activated in pancreatic cancer cells and the JNK inhibitor C66 reduces the inflammatory microenvironment in the tumor. Therefore, the aim of this study was to evaluate the role of C66 in the proliferation and migration of pancreatic cancer. Our results showed that various inflammatory cytokines, such as IL-1β, IL-6, IL-8, and IL-15, were more expressed in pancreatic cancer than in the matching normal tissue. Furthermore, C66, a curcumin analogue with good anti-inflammatory activity, inhibited the proliferation and migration of pancreatic cancer cells in a dose-dependent manner, and effectively inhibited the expression of the above inflammatory factors. Our previous research demonstrated that C66 prevents the inflammatory response by targeting JNK. Therefore, in this study, JNK activity in pancreatic cancer cells was investigated, revealing that JNK was highly activated, and the treatment with C66 inhibited the phosphorylation of JNK. Next, shJNK was used to knockdown JNK expression in pancreatic cancer cells to further confirm the role of JNK in the proliferation and migration of this tumor, as well as in the inflammatory tumor microenvironment (TME). The results demonstrated that JNK knockdown could significantly inhibit the proliferation and migration of pancreatic cancer. Moreover, the low JNK expression in pancreatic cancer cells significantly inhibited the expression of various inflammatory factors. These results indicated that C66 inhibited the progression of pancreatic cancer through the inhibition of JNK-mediated inflammation.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Curcumin Derivative C66 Suppresses Pancreatic Cancer Progression through the Inhibition of JNK-Mediated Inflammation

et al. 2022

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“…The increased knowledge of PDAC genomics, including large-scale studies defining specific omics subtypes has provided insights into key mechanisms of pathogenesis. However, this has not yet been translated to the identification of “actionable” therapeutic targets, or clinically relevant approaches to improving patient care beyond a subgroup of BRCA1-2 or DNA-repair genes mutations [ 13 ].…”

Section: Pancreatic Cancer Chemoresistancementioning

confidence: 99%

Potential Role of Exosomes in the Chemoresistance to Gemcitabine and Nab-Paclitaxel in Pancreatic Cancer

et al. 2022

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In recent years, a growing number of studies have evaluated the role of exosomes in pancreatic ductal adenocarcinoma cancer (PDAC) demonstrating their involvement in a multitude of pathways, including the induction of chemoresistance. The aim of this review is to present an overview of the current knowledge on the role of exosomes in the resistance to gemcitabine and nab-paclitaxel, which are two of the most commonly used drugs for the treatment of PDAC patients. Exosomes are vesicular cargos that transport multiple miRNAs, mRNAs and proteins from one cell to another cell and some of these factors can influence specific determinants of gemcitabine activity, such as the nucleoside transporter hENT1, or multidrug resistance proteins involved in the resistance to paclitaxel. Additional mechanisms underlying exosome-mediated resistance include the modulation of apoptotic pathways, cellular metabolism, or the modulation of oncogenic miRNA, such as miR-21 and miR-155. The current status of studies on circulating exosomal miRNA and their possible role as biomarkers are also discussed. Finally, we integrated the preclinical data with emerging clinical evidence, showing how the study of exosomes could help to predict the resistance of individual tumors, and guide the clinicians in the selection of innovative therapeutic strategies to overcome drug resistance.

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“…We found that circ-MTHFD1L, as an endogenous miR-615-3p sponge, upregulates the expression of RPN6 and then regulates the expression of BRCA1/2, thus exerting its anti-drug effect. Studies have proved that olaparib has practical clinical value for patients with gBRCA mutation [ 21 ]. However, some “Tumors with BRCA-like mutations” have been discovered recently: they do not have BRCA gene mutations, but the molecular mechanism of tumor canceration is similar, so PARP inhibitors are also suitable [ 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

Circular RNA circ-MTHFD1L induces HR repair to promote gemcitabine resistance via the miR-615-3p/RPN6 axis in pancreatic ductal adenocarcinoma

Chen

Wang

et al. 2022

J Exp Clin Cancer Res

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Background Chemoresistance of pancreatic cancer is the main reason for the poor treatment effect of pancreatic cancer patients. Exploring chemotherapy resistance-related genes has been a difficult and hot topic of oncology. Numerous studies implicate the key roles of circular RNAs (circRNAs) in the development of pancreatic cancer. However, the regulation of circRNAs in the process of pancreatic ductal adenocarcinoma (PDAC) chemotherapy resistance is not yet fully clear. Methods Based on the cross-analysis of the Gene Expression Omnibus (GEO) database and the data of our center, we explored a new molecule, hsa_circ_0078297 (circ-MTHFD1L), related to chemotherapy resistance. QRT-PCR was used to detect the expression of circRNAs, miRNAs, and mRNAs in human PDAC tissues and their matched normal tissues. The interaction between circ-MTHFD1L and miR-615-3p/RPN6 signal axis was confirmed by a series of experiments such as Dual-luciferase reporter assay, fluorescence in situ hybridization (FISH) RNA immunoprecipitation (RIP) assays. Results Circ-MTHFD1L was significantly increased in PDAC tissues and cells. And in PDAC patients, the higher the expression level of circ-MTHFD1L, the worse the prognosis. Mechanism analysis showed that circ-MTHFD1L, as an endogenous miR-615-3p sponge, upregulates the expression of RPN6, thereby promoting DNA damage repair and exerting its effect on enhancing gemcitabine chemotherapy resistance. More importantly, we also found that Silencing circ-MTHFD1L combined with olaparib can increase the sensitivity of pancreatic cancer to gemcitabine. Conclusion Circ-MTHFD1L maintains PDAC gemcitabine resistance through the miR-615-3p/RPN6 signal axis. Circ-MTHFD1L may be a molecular marker for the effective treatment of PDAC.

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Treatment opportunities and future perspectives for pancreatic cancer patients with germline BRCA1-2 pathogenic variants

Cited by 20 publications

References 90 publications

Curcumin Derivative C66 Suppresses Pancreatic Cancer Progression through the Inhibition of JNK-Mediated Inflammation

Curcumin Derivative C66 Suppresses Pancreatic Cancer Progression through the Inhibition of JNK-Mediated Inflammation

Potential Role of Exosomes in the Chemoresistance to Gemcitabine and Nab-Paclitaxel in Pancreatic Cancer

Circular RNA circ-MTHFD1L induces HR repair to promote gemcitabine resistance via the miR-615-3p/RPN6 axis in pancreatic ductal adenocarcinoma

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