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Institut Català d'Oncologia

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Javier A. Menéndez

Institut Català d'Oncologia

Elisabet Cuyàs

Institut Català d'Oncologia

Joaquim Bosch‐Barrera

Institut Català d'Oncologia

Begoña Martı́n-Castillo

Institut d'Investigació Biomèdica de Girona

Montse Sánchez‐Céspedes

Josep Carreras Leukaemia Research Institute

Jorge Joven

Institut d'Investigació Sanitària Pere Virgili

Alberto Villanueva

Institut d'Investigació Biomédica de Bellvitge

August Vidal

Institut d'Investigació Biomédica de Bellvitge

Ruth Lupu

Mayo Clinic

Julián Carretero

Universitat de València

Cooperative Institutions

Institut Català d'Oncologia

Institut d'Investigació Biomèdica de Girona

Institut d'Investigació Biomédica de Bellvitge

Hospital Universitari de Girona Doctor Josep Trueta

Universitat de Barcelona

Centro de Investigación Biomédica en Red de Cáncer

Bellvitge University Hospital

University of Girona

Instituto de Salud Carlos III

Catalan Institute for Water Research

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SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade

bioRxiv (Cold Spring Harbor Laboratory) (2020)

Octavio A. Romero Andrea Vilarrubi Juan J. Alburquerque-Béjar Antonio Gómez Álvaro Andrades

Summary Despite the genetic inactivation of SMARCA4 , a core component of the SWI/SNF-complex commonly found in cancer, there are no therapies that effectively target SMARCA4-deficient tumours. Here, we show that, unlike the cells with activated MYC oncogene, cells with SMARCA4 inactivation are refractory to the histone deacetylase inhibitor, SAHA, leading to the aberrant accumulation of H3K27me3. This is associated with impaired transactivation and significantly reduced levels of the histone demethylases KDM6A/UTX and KDM6B/JMJD3, which confer a strong dependency on the KDM6s in the SMARCA4 -mutant cells, so that its inhibition compromises cell viability. Administering the KDM6 inhibitor GSK-J4 to mice orthotopically implanted with SMARCA4 -mutant lung cancer cells or primary small cell carcinoma of the hypercalcaemic type (SCCOHT) had strong anti-tumour effects. Our results highlight the vulnerability of KDM6 inhibitors as a characteristic that could be exploited for treating SMARCA4- mutant cancer patients.

SMARCA4

10.1101/2020.08.07.241232

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Citations (1)

Genome-wide profiling of non-smoking-related lung cancer cells reveals common RB1 rearrangements associated with histopathologic transformation in EGFR-mutant tumors

Annals of Oncology (2020)

Eva Pros María Saigi Daniel Alameda Gema Gómez‐Mariano Beatriz Martínez‐Delgado

T790M

Neoplastic transformation

10.1016/j.annonc.2019.09.001

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Citations (44)

Silibinin Suppresses Tumor Cell-Intrinsic Resistance to Nintedanib and Enhances Its Clinical Activity in Lung Cancer

Cancers (2021)

Joaquim Bosch‐Barrera Sara Verdura J.C. Ruffinelli Enric Carcereny Elia Sais

The anti-angiogenic agent nintedanib has been shown to prolong overall and progression-free survival in patients with advanced non-small-cell lung cancer (NSCLC) who progress after first-line platinum-based chemotherapy and second-line immunotherapy. Here, we explored the molecular basis and the clinical benefit of incorporating the STAT3 inhibitor silibinin—a flavonolignan extracted from milk thistle—into nintedanib-based schedules in advanced NSCLC. First, we assessed the nature of the tumoricidal interaction between nintedanib and silibinin and the underlying relevance of STAT3 activation in a panel of human NSCLC cell lines. NSCLC cells with poorer cytotoxic responses to nintedanib exhibited a persistent, nintedanib-unresponsive activated STAT3 state, and deactivation by co-treatment with silibinin promoted synergistic cytotoxicity. Second, we tested whether silibinin could impact the lysosomal sequestration of nintedanib, a lung cancer cell-intrinsic mechanism of nintedanib resistance. Silibinin partially, but significantly, reduced the massive lysosomal entrapment of nintedanib occurring in nintedanib-refractory NSCLC cells, augmenting the ability of nintedanib to reach its intracellular targets. Third, we conducted a retrospective, observational multicenter study to determine the efficacy of incorporating an oral nutraceutical product containing silibinin in patients with NSCLC receiving a nintedanib/docetaxel combination in second- and further-line settings (n = 59). Overall response rate, defined as the combined rates of complete and partial responses, was significantly higher in the study cohort receiving silibinin supplementation (55%) than in the control cohort (22%, p = 0.011). Silibinin therapy was associated with a significantly longer time to treatment failure in multivariate analysis (hazard ratio 0.43, p = 0.013), despite the lack of overall survival benefit (hazard ratio 0.63, p = 0.190). Molecular mechanisms dictating the cancer cell-intrinsic responsiveness to nintedanib, such as STAT3 activation and lysosomal trapping, are amenable to pharmacological intervention with silibinin. A prospective, powered clinical trial is warranted to confirm the clinical relevance of these findings in patients with advanced NSCLC.

Nintedanib

Silibinin

10.3390/cancers13164168

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Sensitization of retinoids and corticoids to epigenetic drugs in MYC-activated lung cancers by antitumor reprogramming

Oncogene (2016)

Octavio A. Romero Sara Verdura Manuel Torres-Diz Antonio Gómez Sebastián Moran

Reprogramming

Epigenetic Therapy

10.1038/onc.2016.296

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Citations (9)

Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity

Aging (2020)

Sara Verdura Elisabet Cuyàs Èric Cortada Joan Brunet Eugeni López‐Bonet

New strategies to block the immune evasion activity of programmed death ligand-1 (PD-L1) are urgently needed.When exploring the PD-L1-targeted effects of mechanistically diverse metabolism-targeting drugs, exposure to the dietary polyphenol resveratrol (RSV) revealed its differential capacity to generate a distinct PD-L1 electrophoretic migration pattern.Using biochemical assays, computer-aided docking/molecular dynamics simulations, and fluorescence microscopy, we found that RSV can operate as a direct inhibitor of glyco-PD-L1-processing enzymes (α-glucosidase/α-mannosidase) that modulate N-linked glycan decoration of PD-L1, thereby promoting the endoplasmic reticulum retention of a mannose-rich, abnormally glycosylated form of PD-L1.RSV was also predicted to interact with the inner surface of PD-L1 involved in the interaction with PD-1, almost perfectly occupying the target space of the small compound BMS-202 that binds to and induces dimerization of PD-L1.The ability of RSV to directly target PD-L1 interferes with its stability and trafficking, ultimately impeding its targeting to the cancer cell plasma membrane.Impedance-based real-time cell analysis (xCELLigence) showed that cytotoxic T-lymphocyte activity was notably exacerbated when cancer cells were previously exposed to RSV.This unforeseen immunomodulating mechanism of RSV might illuminate new approaches to restore T-cell function by targeting the PD-1/PD-L1 immunologic checkpoint with natural polyphenols.

Docking (animal)

10.18632/aging.102646

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Citations (124)

Producción de gonadotropinas recombinantes de lenguado Senegalés (Solea senegalensis) para el control de la reproducción

Sara Verdura François Chauvigné María J. Mazón Silvia Zanuy Ana Gómez

XIII Congreso Nacional de Acuicultura. En equilibrio con el medio ambiente. 21-24 noviembre 2011, Barcelona

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Supplementary Methods from <i>PARD3</i> Inactivation in Lung Squamous Cell Carcinomas Impairs STAT3 and Promotes Malignant Invasion

Ester Bonastre Sara Verdura Ilse Zondervan Federica Facchinetti Sylvie Lantuéjoul

<p>Supplementary Materials and Methods</p>

10.1158/0008-5472.22406964.v1

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Heregulin Drives Endocrine Resistance by Altering IL-8 Expression in ER-Positive Breast Cancer

International Journal of Molecular Sciences (2020)

Adriana Papadimitropoulou Luciano Vellón Ella Atlas Travis Vander Steen Elisabet Cuyàs

Sustained HER2/HER3 signaling due to the overproduction of the HER3 ligand heregulin (HRG) is proposed as a key contributor to endocrine resistance in estrogen receptor-positive (ER+) breast cancer. The molecular mechanisms linking HER2 transactivation by HRG-bound HER3 to the acquisition of a hormone-independent phenotype in ER+ breast cancer is, however, largely unknown. Here, we explored the possibility that autocrine HRG signaling drives cytokine-related endocrine resistance in ER+ breast cancer cells. We used human cytokine antibody arrays to semi-quantitatively measure the expression level of 60 cytokines and growth factors in the extracellular milieu of MCF-7 cells engineered to overexpress full-length HRGβ2 (MCF-7/HRG cells). Interleukin-8 (IL-8), a chemokine closely linked to ER inaction, emerged as one the most differentially expressed cytokines. Cytokine profiling using structural deletion mutants lacking both the N-terminus and the cytoplasmic-transmembrane region of HRGβ2—which is not secreted and cannot transactivate HER2—or lacking a nuclear localization signal at the N-terminus—which cannot localize at the nucleus but is actively secreted and transactivates HER2—revealed that the HRG-driven activation of IL-8 expression in ER+ cells required HRG secretion and transactivation of HER2 but not HRG nuclear localization. The functional blockade of IL-8 with a specific antibody inversely regulated ERα-driven transcriptional activation in endocrine-sensitive MCF-7 cells and endocrine-resistant MCF-7/HRG cells. Overall, these findings suggest that IL-8 participates in the HRG-driven endocrine resistance program in ER+/HER2- breast cancer and might illuminate a potential clinical setting for IL8- or CXCR1/2-neutralizing antibodies.

10.3390/ijms21207737

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Citations (11)

Fatty acid synthase (FASN) regulates the mitochondrial priming of cancer cells

Cell Death and Disease (2021)

Barbara Schroeder Travis Vander Steen Ingrid Espinoza Chandra M. K. Venkatapoorna Zeng Hu

Abstract Inhibitors of the lipogenic enzyme fatty acid synthase (FASN) have attracted much attention in the last decade as potential targeted cancer therapies. However, little is known about the molecular determinants of cancer cell sensitivity to FASN inhibitors (FASNis), which is a major roadblock to their therapeutic application. Here, we find that pharmacological starvation of endogenously produced FAs is a previously unrecognized metabolic stress that heightens mitochondrial apoptotic priming and favors cell death induction by BH3 mimetic inhibitors. Evaluation of the death decision circuits controlled by the BCL-2 family of proteins revealed that FASN inhibition is accompanied by the upregulation of the pro-death BH3-only proteins BIM, PUMA, and NOXA. Cell death triggered by FASN inhibition, which causally involves a palmitate/NADPH-related redox imbalance, is markedly diminished by concurrent loss of BIM or PUMA, suggesting that FASN activity controls cancer cell survival by fine-tuning the BH3 only proteins-dependent mitochondrial threshold for apoptosis. FASN inhibition results in a heightened mitochondrial apoptosis priming, shifting cells toward a primed-for-death state “addicted” to the anti-apoptotic protein BCL-2. Accordingly, co-administration of a FASNi synergistically augments the apoptosis-inducing activity of the dual BCL-X L /BCL-2 inhibitor ABT-263 (navitoclax) and the BCL-2 specific BH3-mimetic ABT-199 (venetoclax). FASN inhibition, however, fails to sensitize breast cancer cells to MCL-1- and BCL-X L -selective inhibitors such as S63845 and A1331852. A human breast cancer xenograft model evidenced that oral administration of the only clinically available FASNi drastically sensitizes FASN-addicted breast tumors to ineffective single-agents navitoclax and venetoclax in vivo. In summary, a novel FASN-driven facet of the mitochondrial priming mechanistically links the redox-buffering mechanism of FASN activity to the intrinsic apoptotic threshold in breast cancer cells. Combining next-generation FASNis with BCL-2-specific BH3 mimetics that directly activate the apoptotic machinery might generate more potent and longer-lasting antitumor responses in a clinical setting.

Puma

Priming (agriculture)

10.1038/s41419-021-04262-x

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Citations (58)

In silico clinical trials for anti-aging therapies

Aging (2019)

Javier A. Menéndez Elisabet Cuyàs Núria Folguera-Blasco Sara Verdura Begoña Martı́n-Castillo

A growing aging population burdened by multiple chronic diseases and geriatric syndromes has escalated to become a major public health and medical challenge in Western society [1].Elderly individuals who are frail are less able to cope with physiological stressors, and not only experience suboptimal health outcomes but www.aging-us.com

Reprogramming

Senescence

10.18632/aging.102180

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Citations (4)