Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest types of cancer and the chemotherapies such as gemcitabine/nab-paclitaxel are confronted with intrinsic or acquired resistance. The aim of this study was to investigate mechanisms underlying paclitaxel resistance in PDAC and explore strategies to overcome it.
Methods: Three paclitaxel (PR) and gemcitabine resistant (GR) PDAC models were established. Transcriptomics and proteomics were used to identify conserved mechanisms of drug resistance. Genetic and pharmacological approaches were used to overcome paclitaxel resistance.
Results: Upregulation of ABCB1 through locus amplification was identified as a conserved feature unique to PR cells. ABCB1 was not affected in any of the GR models and no cross resistance was observed. The ABCB1 inhibitor verapamil or siRNA-mediated ABCB1 depletion sensitized PR cells to paclitaxel and prevented efflux of ABCB1 substrates in all models. ABCB1 expression was associated with a trend towards shorter survival in patients who had received gemcitabine/nab-paclitaxel treatment. A pharmacological screen identified known and novel kinase inhibitors that attenuate efflux of ABCB1 substrates and sensitize PR PDAC cells to paclitaxel.
Conclusion: Upregulation of ABCB1 through locus amplification represents a novel, conserved mechanism of PDAC paclitaxel resistance. Kinase inhibitors identified in this study can be further (pre) clinically explored as therapeutic strategies to overcome paclitaxel resistance in PDAC.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10759666 | PMC |
| http://dx.doi.org/10.1186/s13046-023-02879-8 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Inosine monophosphate dehydrogenase 2 (IMPDH2) modulates response to therapy and chemo-resistance in triple negative breast cancer.
Sci Rep
January 2025
Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, CGP L3-317, Buffalo, NY, 14263, USA.
Triple negative breast cancer (TNBC) is one of the deadliest subtypes of breast cancer, whose high frequency of relapse is often due to resistance to chemotherapy. Here, we identify inosine monophosphate dehydrogenase 2 (IMPDH2) as a contributor to doxorubicin resistance, in multiple TNBC models. Analysis of publicly available datasets reveals elevated IMPDH2 expression to associate with worse overall TNBC prognosis in the clinic, including lower recurrence-free survival post adjuvant/neoadjuvant therapy.
View Article and Find Full Text PDFUse of Gain-of-Function Screening to Identify miRNAs Involved in Paclitaxel Resistance in Triple-Negative Breast Cancer.
Int J Mol Sci
December 2024
Molecular Oncology Group, Biogipuzkoa Health Research Institute, 20014 San Sebastian, Spain.
Paclitaxel is a widely used chemotherapeutic agent for the treatment of breast cancer (BC), including as a front-line treatment for triple-negative breast cancer (TNBC) patients. However, resistance to paclitaxel remains one of the major causes of death associated with treatment failure. Multiple studies have demonstrated that miRNAs play a role in paclitaxel resistance and are associated with both disease progression and metastasis.
View Article and Find Full Text PDFPLGA-Nano-Encapsulated Disulfiram Inhibits Cancer Stem Cells and Targets Non-Small Cell Lung Cancer In Vitro and In Vivo.
Biomolecules
December 2024
Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton WV1 1LY, UK.
Cancer stem cells (CSCs) play a key role in non-small cell lung cancer (NSCLC) chemoresistance and metastasis. In this study, we used two NSCLC cell lines to investigate the regulating effect of hypoxia in the induction and maintenance of CSC traits. Our study demonstrated hypoxia-induced stemness and chemoresistance at levels comparable to those in typical CSC sphere culture.
View Article and Find Full Text PDFHarnessing the anticancer potential of Piper nigrum: a synergistic approach to chemotherapy enhancement and reduced side effects.
Discov Oncol
January 2025
Universidad Espíritu Santo, Samborondón, 092301, Ecuador.
Article Synopsis
- Cancer therapy faces issues like drug resistance and severe side effects, prompting exploration of novel, cost-effective treatments like Piper nigrum (black pepper) extract as a complementary anticancer agent.
- Piper nigrum contains bioactive compounds such as piperine that show significant anticancer effects, including tumor inhibition and enhancing the effectiveness of traditional chemotherapy while reducing side effects.
- The review identifies challenges such as variability and bioavailability of PNE, underscoring the need for further research to validate its use in clinical settings and improve cancer treatment outcomes.
Chemotherapy-Induced Cell-Surface GRP78 Expression as a Prognostic Marker for Invasiveness of Metastatic Triple-Negative Breast Cancer.
Ann Biomed Eng
January 2025
Faculty of Biomedical Engineering, Technion-Israel Institute of Technology, 3200003, Haifa, Israel.
Article Synopsis
- Metastasis is responsible for 90% of cancer-related deaths, particularly in triple-negative breast cancer (TNBC), making it essential to understand molecular drivers to find better prognostic markers after chemotherapy.
- Current chemotherapy treatments like doxorubicin and paclitaxel affect tumor cells in various ways, including activating the unfolded protein response (UPR), with GRP78 playing a significant but controversial role in metastasis.
- The study identifies subpopulations of GRP78+ and GRP78- cells in TNBC, demonstrating that while GRP78- cells are more invasive, the combination of both subpopulations may influence overall metastatic potential, offering insights for personalized cancer treatment strategies.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!