Biology subjects

Fernandez-Lozano, C.

Publications and source records attributed to Fernandez-Lozano, C..

3 recordsLinked to original sources

bioRxiv2026

Heterogeneous graph neural networks with biological prior knowledge for interpretable drug repurposing in triple-negative breast cancer

Drug repurposing offers a cost-effective path to new therapies for triple-negative breast cancer (TNBC), a subtype with limited targeted treatment options. We present PRECISION, a framework integrating transcription factor (TF) regulatory networks, protein-protein interactions, and drug-target edges into a heterogeneous graph neural network (GNN) to identify TFs mediating drug sensitivity and prioritize repurposing candidates. The knowledge graph has 23,498 nodes and approximately 830,000 edges from CollecTRI, OmniPath and the PRISM screen. In a fair cell-line hold-out evaluation, the GNN matches ML baselines in global prediction (Pearson r = 0.76). Per-drug mechanistic attributions via Integrated Gradients on the trained GNN, replicated across three independent training seeds and robust to baseline choice (Spearman's rho = 0.94 between the mean and the random Gaussian baselines), highlight stress-response (CREB3L1), epithelial-mesenchymal transition (EMT; KLF8, ZEB1), stromal/TNBC-specific (AEBP1, MZF1), and epithelial (SPDEF) regulators as stable mediators of drug response. Multi-cohort validation in SCAN-B (n = 7,397), METABRIC (n = 1,979), and TCGA-BRCA (n = 1,072) shows that predicted drug sensitivity is associated with overall survival in 623 drugs in SCAN-B and 74 in METABRIC (FDR < 0.05). Fisher's meta-analysis identifies 551 drugs at FDR < 0.05, validated by positive controls paclitaxel (p_adj = 8.6x10-3), docetaxel (3.1x10-2), epirubicin (3.2x10-6), and talazoparib (1.4x10-4). Paired Wilcoxon tests in 39 AURORA-US patients with matched primary and metastatic samples confirm that 4 of the 10 IG-identified TFs (CREB3L1, KLF8, AEBP1, SPDEF) are significantly altered during metastatic progression after Bonferroni correction. An explicit rule applied to the PAM50-adjusted Cox multivariate results (penalizer = 0.1) selects seven candidates (osimertinib, saracatinib, erlotinib, brigatinib, pelitinib, entinostat, trametinib), revealing pharmacological convergence on the EGFR signaling axis.

bioinformatics↗

bioRxiv2025

Transcriptomic signature reveals sensitivity to tubulin inhibitors in colon cancer

Colon cancer is the second most common cause of cancer death worldwide. Despite advances in the development of new molecular strategies for stratifying patients with colon cancer, many of these patients do not respond adequately to the standard of care. While previous studies have focused on the development of prognostic gene expression signatures, the exploration of predictive signatures to inform treatment decisions remains incomplete. In this study, we leveraged public gene expression datasets to design and experimentally validate a 37-gene expression signature for prognosis in colon cancer patients. We obtained a C-index of 0.732 (0.610-0.853) in four independent studies. Specifically, we discovered that the signature is associated with the mitotic phase of the cell cycle. Furthermore, the signature identified a population of colon cancer patients sensitive to tubulin inhibitor drugs. In particular, we validated in vitro and in vivo the efficacy of paclitaxel, a commonly used tubulin inhibitor in breast cancer treatment, in patient-derived preclinical models. These results highlight the importance of incorporating gene expression signatures to identify new therapeutic options for colon cancer treatment. Furthermore, the identification of alternative treatment options with potentially improved efficacy holds promise for the development of new clinical trials, and reshapes the biomarker-based treatment strategy for second line and refractory colon cancer patients.

cancer biology↗

bioRxiv2024

Cx43 Enhances Response to BRAF/MEK Inhibitors by Reducing DNA Repair Capacity

BRAF and MEK inhibitors (BRAF/MEKi) have radically changed the treatment landscape of advanced BRAF mutation-positive tumours. However, limited efficacy and emergence of drug resistance are major handicaps for successful treatments. Here, by using relevant preclinical models, we found that Connexin43 (Cx43), a protein that plays a role in cell-to-cell communication, increases effectiveness of BRAF/MEKi by recruiting DNA repair complexes to lamin-associated domains and promoting persistent DNA damage and cellular senescence. The nuclear compartmentalization promoted by Cx43 contributes to genome instability and synthetic lethality caused by excessive DNA damage, which could lead to a novel therapeutic approach for these tumours to overcome drug resistance. Based on these findings, we designed an innovative drug combination using small extracellular vesicles (sEVs) to deliver the full-Cx43 in combination with the BRAF/MEKi. This study reveals Cx43 as a new player on DNA repair and BRAF/MEKi response, underlining the therapeutical potential that this approach could eventually have in the clinic to overcome the limitations of current therapies and improve treatment outcomes for patients with advanced BRAF mutant tumours.

cancer biology↗