Overcoming PLK1 inhibitor resistance by targeting mevalonate pathway to impair AXL-TWIST axis in colorectal cancer

Solanes-Casado, Sonia; Cebrián, Arancha; Rodríguez‐Remírez, María; Mahíllo, Ignacio; García-García, Laura; Río-Vilariño, Anxo; Baños, Natalia; Cárcer, Guillermo de; Monfort-Vengut, Ana; Castellano, V.; Fernández-Aceñero, M. Jesús; García‐Foncillas, Jesús; Puerto‐Nevado, Laura del

doi:10.1016/j.biopha.2021.112347

Cited by 12 publications

(7 citation statements)

References 39 publications

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“… 66 Its downstream signaling is mediated by Twist1, which activates the expression of gene programs that may lead to PLK1 inhibitor resistance via EMT and activates the transcriptional regulation of ABCB1 , which encodes the multidrug resistance protein MDR1, also known as P-glycoprotein (P-gp). Solanes-Casado et al 67 further confirmed the EMT process in drug-resistant colorectal cancer cells is driven by AXL signaling and Twist1 as part of their acquired drug resistance mechanism by assessing the expression levels of Ax1 , Twist1 , E-calmodulin , vimentin , ABCB1 , and MDR1 in colorectal cancer cell lines that are PLK inhibitor BI2536-resistant and parental cell lines without detectable mutations in HT29, SW837, and HCT116. In addition, Solanes-Casado et al 67 found that mdr1 expression was significantly higher in BI2536-resistant cell lines than in parental cell lines at both the mRNA and protein levels.…”

Section: Treatment and Drug Resistance Of Crc Associated With Emtmentioning

confidence: 93%

“…Solanes-Casado et al 67 further confirmed the EMT process in drug-resistant colorectal cancer cells is driven by AXL signaling and Twist1 as part of their acquired drug resistance mechanism by assessing the expression levels of Ax1 , Twist1 , E-calmodulin , vimentin , ABCB1 , and MDR1 in colorectal cancer cell lines that are PLK inhibitor BI2536-resistant and parental cell lines without detectable mutations in HT29, SW837, and HCT116. In addition, Solanes-Casado et al 67 found that mdr1 expression was significantly higher in BI2536-resistant cell lines than in parental cell lines at both the mRNA and protein levels. The variation in protein increased 6- to 50-fold, while mRNA expression was 200-fold in the BI2536-resistant lines compared to the parental lines.…”

Section: Treatment and Drug Resistance Of Crc Associated With Emtmentioning

confidence: 93%

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Research Progress of Epithelial-mesenchymal Transition Treatment and Drug Resistance in Colorectal Cancer

2022

Technol Cancer Res Treat

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Colorectal cancer (CRC) is one of the most common malignancies in the world that seriously affects human health. Activation of epithelial-mesenchymal transition (EMT) is a physiological phenomenon during embryonic development that is essential for cell metastasis. EMT participates in various biological processes associated with trauma repair, organ fibrosis, migration, metastasis, and infiltration of tumor cells. EMT is a new therapeutic target for CRC; however, some patients with CRC develop resistance to some drugs due to EMT. This review focuses specifically on the status of treatments that target the EMT process and its role in the therapeutic resistance observed in patients with CRC.

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Section: Treatment and Drug Resistance Of Crc Associated With Emtmentioning

confidence: 93%

Section: Treatment and Drug Resistance Of Crc Associated With Emtmentioning

confidence: 93%

Research Progress of Epithelial-mesenchymal Transition Treatment and Drug Resistance in Colorectal Cancer

2022

Technol Cancer Res Treat

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“…The detailed protocol of RNA extraction and RT-qPCR was reported previously [ 20 ]. TaqMan® probes (Thermo Fisher Scientific) used for evaluating gene expression are the following: CYR61 (Hs00155479_m1), CTGF (Hs00170014_m1), SOX2 (Hs04234836_s1), RPLP0 (Hs99999902_m1).…”

Section: Methodsmentioning

confidence: 99%

“…Western blotting protocol was performed as previously described [ 20 ]. 20–30 µg of protein lysate was used in each experiment.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of the AURKA/YAP1 axis is a promising therapeutic option for overcoming cetuximab resistance in colorectal cancer stem cells

Rio-Vilariño,

Cenigaonandia-Campillo,

García-Bautista

et al. 2024

Br J Cancer

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Background Primary resistance to anti-EGFR therapies affects 40% of metastatic colorectal cancer patients harbouring wild-type RAS/RAF. YAP1 activation is associated with this resistance, prompting an investigation into AURKA’s role in mediating YAP1 phosphorylation at Ser397, as observed in breast cancer. Methods We used transcriptomic analysis along with in vitro and in vivo models of RAS/RAF wild-type CRC to study YAP1 Ser397 phosphorylation as a potential biomarker for cetuximab resistance. We assessed cetuximab efficacy using CCK8 proliferation assays and cell cycle analysis. Additionally, we examined the effects of AURKA inhibition with alisertib and created a dominant-negative YAP1 Ser397 mutant to assess its impact on cancer stem cell features. Results The RAS/RAF wild-type CRC models exhibiting primary resistance to cetuximab prominently displayed elevated YAP1 phosphorylation at Ser397 primarily mediated by AURKA. AURKA-induced YAP1 phosphorylation was identified as a key trigger for cancer stem cell reprogramming. Consequently, we found that AURKA inhibition had the capacity to effectively restore cetuximab sensitivity and concurrently suppress the cancer stem cell phenotype. Conclusions AURKA inhibition holds promise as a therapeutic approach to overcome cetuximab resistance in RAS/RAF wild-type colorectal cancer, offering a potential means to counter the development of cancer stem cell phenotypes associated with cetuximab resistance.

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“…Similarly, Feng et al (33) showed that simvastatin enhanced sorafenib efficacy by suppressing pyruvate kinase muscle isozyme M2-mediated glycolysis, thus increasing apoptosis, and reducing cell proliferation, effectively re-sensitizing HCC cells to sorafenib. Solanes-Casado et al (34) showed that combination treatment with simvastatin and volasertib, another small-molecule inhibitor, provokes inactivation of ATP-binding cassette subfamily B member 1, which inhibits its function and allows volasertib to accumulate in the cell, triggering apoptosis by inhibiting polo-like kinase 1, which normally induces chemoresistance. Additionally, Gupta et al (35) observed that cells with increased CD133 expression also had increased cholesterol content, hence pancreatic cancer cells that had increased CD133 were more responsive to lovastatin compared to those that had lower expression.…”

Section: Statins Aid In Chemosensitization and Prevention Of Chemores...mentioning

confidence: 99%

The Influence of Statin Use on Chemotherapeutic Efficacy in Studies of Mouse Models: A Systematic Review

TULK,

WATSON,

ERDRICH

2023

Anticancer Res

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Background/Aim: Using statins as antitumor agents is an approach to cancer therapy that has been explored extensively in specific cancer types. Reframing the query to how a statin interacts with the treatment regimen instead might provide new insight. Given that cell-cycle regulation influences tumorigenesis, it is possible that the cellcycle phase which a given chemotherapy acts on influences the synergistic effects with adjuvant statin use. In this review, we outline the effect of statins in combination with chemotherapeutic drugs in in vivo animal model studies based on the class of chemotherapy and its relation to the cell cycle. Materials and Methods: This systematic review was conducted using the Preferred Reporting Items for Systematic reviews and Meta-Analyses for Protocols 2015 with 23 articles deemed eligible to be included. Results: Our review suggests that statins influence the success of chemotherapy treatments. Furthermore, enhanced efficacy was demonstrated with chemotherapeutic drugs that act at every phase of the cell cycle. Conclusion: This type of compilation departs from the norm of describing statin influence on named cancer subtypes and instead catalogs how statins interact with categorical chemotherapy agents which might be beneficial for broader therapeutic decision-making across cancer subtypes, possibly contributing to pharmaceutical development, and thereby helping to maximize patient outcomes.

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Overcoming PLK1 inhibitor resistance by targeting mevalonate pathway to impair AXL-TWIST axis in colorectal cancer

Cited by 12 publications

References 39 publications

Research Progress of Epithelial-mesenchymal Transition Treatment and Drug Resistance in Colorectal Cancer

Research Progress of Epithelial-mesenchymal Transition Treatment and Drug Resistance in Colorectal Cancer

Inhibition of the AURKA/YAP1 axis is a promising therapeutic option for overcoming cetuximab resistance in colorectal cancer stem cells

The Influence of Statin Use on Chemotherapeutic Efficacy in Studies of Mouse Models: A Systematic Review

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