Aurora kinase A drives non-canonical YAP1/TAZ crosstalk to sustain primary resistance to anti-EGFR therapies in colorectal cancer

Anti-epidermal growth factor receptor (EGFR) therapies are the most recommended first-line treatment for RAS/RAF wild-type unresectable metastatic colorectal cancer (CRC) according to the European Society for Medical Oncology guidelines. However, primary resistance renders this treatment ineffective for almost 40% of patients. Our previous work identified Aurora kinase A (AURKA) as a key resistance driver through non-canonical, Hippo-independent Yes-associated protein 1 (YAP1) activation. However, the role of the other main Hippo coactivator, transcriptional coactivator with PDZ-binding motif (TAZ), in this resistance mechanism remains unexplored. By integrating preclinical in vitro and in vivo models, including cell lines and patient-derived xenografts, with RNA sequencing, we investigated the impact of TAZ overexpression in cetuximab resistance driven by the AURKA/YAP1 axis. Our findings reveal that TAZ overexpression sustains YAP1-mediated resistance and stemness. Even under YAP1 suppression, TAZ-overexpressing cells remain unresponsive to anti-EGFR therapies, whereas dual YAP1/TAZ silencing restores sensitivity. Treatment with alisertib, a phase III AURKA inhibitor, simultaneously destabilizes YAP1 and TAZ, restoring anti-EGFR efficacy by suppressing stemness. Transcriptomic analyses further show that AURKA inhibition and dual YAP1/TAZ suppression disrupt stem-like traits and reveal transcriptional deregulations affecting nucleotide metabolism. These findings demonstrate that AURKA orchestrates YAP1/TAZ crosstalk, which is crucial for driving stemness and resistance to anti-EGFR therapies, highlighting AURKA inhibitors as a promising strategy to enhance anti-EGFR therapies in metastatic CRC.Psicología y Ciencias de la Salu

Vitamin-C-dependent downregulation of the citrate metabolism pathway potentiates pancreatic ductal adenocarcinoma growth arrest

In pancreatic ductal adenocarcinoma (PDAC), metabolic rewiring and resistance to standard therapy are closely associated. PDAC cells show enormous requirements for glucose-derived citrate, the first rate-limiting metabolite in the synthesis of new lipids. Both the expression and activity of citrate synthase (CS) are extraordinarily upregulated in PDAC. However, no previous relationship between gemcitabine response and citrate metabolism has been documented in pancreatic cancer. Here, we report for the first time that pharmacological doses of vitamin C are capable of exerting an inhibitory action on the activity of CS, reducing glucose-derived citrate levels. Moreover, ascorbate targets citrate metabolism towards the de novo lipogenesis pathway, impairing fatty acid synthase (FASN) and ATP citrate lyase (ACLY) expression. Lowered citrate availability was found to be directly associated with diminished proliferation and, remarkably, enhanced gemcitabine response. Moreover, the deregulated citrate-derived lipogenic pathway correlated with a remarkable decrease in extracellular pH through inhibition of lactate dehydrogenase (LDH) and overall reduced glycolytic metabolism. Modulation of citric acid metabolism in highly chemoresistant pancreatic adenocarcinoma, through molecules such as vitamin C, could be considered as a future clinical option to improve patient response to standard chemotherapy regimens.Medicin

Medullary Thyroid Carcinoma Running Title: Association of RET, ARTN and GFRα1 with sMTC

*These authors contributed equally to this work Keywords: GFRα-RET complex, risk of developing MTC, Polymorphisms, haplotypes Copyright (C) 2005 by The Endocrine Society Context. Medullary thyroid carcinoma is a characteristic tumour occurring in individuals with multiple endocrine neoplasia type 2, who carry germ line mutations in RET. However, most MTC occur in individuals without family history. Objectives. To explore the possibility that susceptibility in these cases results from low penetrance alleles of RET, its co-receptors and ligands. Design. We carried out an association study in 135 sporadic MTC (sMTC) and 533 controls from the UK-population. Results and conclusions. We analyzed 33 polymorphisms in all 9 genes involved in the GFRα-RET complex. This is the first association study in which all genes involved in this complex have been investigated for susceptibility to sMTC. We did not find any association between SNPs in the exonic regions of the GFRα2, GFRα3, GFRα4, GDNF, NRTN or PSPN genes and risk of developing sMTC. We found a strong association between the disease and specific haplotypes of RET. We have not only confirme

Data from Tagging Single-Nucleotide Polymorphisms in Antioxidant Defense Enzymes and Susceptibility to Breast Cancer

&lt;div&gt;Abstract&lt;p&gt;It is generally believed that the initiation of breast cancer is a consequence of cumulative genetic damage leading to genetic alterations and provoking uncontrolled cellular proliferation and/or aberrant programmed cell death, or apoptosis. Reactive oxygen species have been related to the etiology of cancer as they are known to be mitogenic and therefore capable of tumor promotion. The aim of this study was to assess the role of common variation in 10 polymorphic genes coding for antioxidant defense enzymes in modulating individual susceptibility to breast cancer using a case-control study (&lt;i&gt;N&lt;/i&gt; cases = 4,474 and &lt;i&gt;N&lt;/i&gt; controls = 4,580). Both cases and controls were from the East Anglian region of the United Kingdom. We have identified a set of 54 single nucleotide polymorphisms (SNPs) that efficiently tag all the known SNPs in the 10 genes and are also expected to tag any unknown SNPs in each gene. We found no evidence for association of common variants in &lt;i&gt;SOD1, SOD2, GPX1, GPX4, GSR, TXNRD1&lt;/i&gt;, and &lt;i&gt;TXN2&lt;/i&gt;. There was borderline evidence for association of variants in &lt;i&gt;CAT g&lt;/i&gt;27168&lt;i&gt;a&lt;/i&gt; {&lt;i&gt;P&lt;/i&gt; [2 degrees of freedom (&lt;i&gt;df&lt;/i&gt;)] = 0.05}, &lt;i&gt;TXN t&lt;/i&gt;2715&lt;i&gt;c&lt;/i&gt; [&lt;i&gt;P&lt;/i&gt; (2 &lt;i&gt;df&lt;/i&gt;) = 0.007], and &lt;i&gt;TXNRD2&lt;/i&gt; A66S and &lt;i&gt;TXNRD2 g&lt;/i&gt;23524&lt;i&gt;a&lt;/i&gt; (&lt;i&gt;P&lt;/i&gt;&lt;sub&gt;trend&lt;/sub&gt; = 0.074 and 0.046, respectively). For &lt;i&gt;TXNRD2&lt;/i&gt; A66S [AS versus AA: odds ratio (OR), 1.05; 95% confidence intervals (95% CI), 0.96-1.15; SS versus AA: OR, 1.12; 95% CI, 0.98-1.29], there are bioinformatics data to suggest that it is functional but confirmation in independent data sets is required before they can be regarded as definitive breast cancer susceptibility alleles. Even if confirmed, these four alleles would account for just 0.32% of the excess familial risk of breast cancer. (Cancer Res 2006; 66(2): 1225-33)&lt;/p&gt;&lt;/div&gt;</jats:p