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Bertotti Colorectal EGFR

Gabriele Picco, Consalvo Petti, Francesco Sassi, Katia Grillone, Giorgia Migliardi, Teresa Rossi, Claudio Isella, Federica Di Nicolantonio, Ivana Sarotto, Anna Sapino, Alberto Bardelli, Livio Trusolino, Andrea Bertotti, Enzo Medico
BACKGROUND: The NEDD8 conjugation pathway modulates the ubiquitination and activity of a wide range of intracellular proteins, and its blockade by pevonedistat is emerging as a promising therapeutic approach in various cancer settings. However, systematic characterization of pevonedistat efficacy in specific tumor types and definition of response predictors are still missing. METHODS: We investigated in vitro sensitivity to pevonedistat in 122 colorectal cancer (CRC) cell lines by an ATP-based proliferation assay and evaluated apoptosis and DNA content by flow cytometry...
February 2017: Journal of the National Cancer Institute
Valerio Gelfo, Maria Teresa Rodia, Michela Pucci, Massimiliano Dall'Ora, Spartaco Santi, Rossella Solmi, Lee Roth, Moshit Lindzen, Massimiliano Bonafè, Andrea Bertotti, Elisabetta Caramelli, Pier-Luigi Lollini, Livio Trusolino, Yosef Yarden, Gabriele D'Uva, Mattia Lauriola
Epidermal Growth Factor Receptor (EGFR) activates a robust signalling network to which colon cancer tumours often become addicted. Cetuximab, one of the monoclonal antibodies targeting this pathway, is employed to treat patients with colorectal cancer. However, many patients are intrinsically refractory to this treatment, and those who respond develop secondary resistance along time. Mechanisms of cancer cell resistance include either acquisition of new mutations or non genomic activation of alternative signalling routes...
September 30, 2016: Oncotarget
Sabrina Arena, Giulia Siravegna, Benedetta Mussolin, Jeffrey D Kearns, Beni B Wolf, Sandra Misale, Luca Lazzari, Andrea Bertotti, Livio Trusolino, Alex A Adjei, Clara Montagut, Federica Di Nicolantonio, Rachel Nering, Alberto Bardelli
The anti-epidermal growth factor receptor (EGFR) antibodies cetuximab and panitumumab are used to treat RAS wild-type colorectal cancers (CRCs), but their efficacy is limited by the emergence of acquired drug resistance. After EGFR blockade, about 20% of CRCs develop mutations in the EGFR extracellular domain (ECD) that impair antibody binding and are associated with clinical relapse. We hypothesized that EGFR ECD-resistant variants could be targeted by the recently developed oligoclonal antibody MM-151 that binds multiple regions of the EGFR ECD...
February 3, 2016: Science Translational Medicine
Andrea Bertotti, Eniko Papp, Siân Jones, Vilmos Adleff, Valsamo Anagnostou, Barbara Lupo, Mark Sausen, Jillian Phallen, Carolyn A Hruban, Collin Tokheim, Noushin Niknafs, Monica Nesselbush, Karli Lytle, Francesco Sassi, Francesca Cottino, Giorgia Migliardi, Eugenia R Zanella, Dario Ribero, Nadia Russolillo, Alfredo Mellano, Andrea Muratore, Gianluca Paraluppi, Mauro Salizzoni, Silvia Marsoni, Michael Kragh, Johan Lantto, Andrea Cassingena, Qing Kay Li, Rachel Karchin, Robert Scharpf, Andrea Sartore-Bianchi, Salvatore Siena, Luis A Diaz, Livio Trusolino, Victor E Velculescu
Colorectal cancer is the third most common cancer worldwide, with 1.2 million patients diagnosed annually. In late-stage colorectal cancer, the most commonly used targeted therapies are the monoclonal antibodies cetuximab and panitumumab, which prevent epidermal growth factor receptor (EGFR) activation. Recent studies have identified alterations in KRAS and other genes as likely mechanisms of primary and secondary resistance to anti-EGFR antibody therapy. Despite these efforts, additional mechanisms of resistance to EGFR blockade are thought to be present in colorectal cancer and little is known about determinants of sensitivity to this therapy...
October 8, 2015: Nature
Sandra Misale, Ivana Bozic, Jingshan Tong, Ashley Peraza-Penton, Alice Lallo, Federica Baldi, Kevin H Lin, Mauro Truini, Livio Trusolino, Andrea Bertotti, Federica Di Nicolantonio, Martin A Nowak, Lin Zhang, Kris C Wood, Alberto Bardelli
Molecular targeted drugs are clinically effective anti-cancer therapies. However, tumours treated with single agents usually develop resistance. Here we use colorectal cancer (CRC) as a model to study how the acquisition of resistance to EGFR-targeted therapies can be restrained. Pathway-oriented genetic screens reveal that CRC cells escape from EGFR blockade by downstream activation of RAS-MEK signalling. Following treatment of CRC cells with anti-EGFR, anti-MEK or the combination of the two drugs, we find that EGFR blockade alone triggers acquired resistance in weeks, while combinatorial treatment does not induce resistance...
September 22, 2015: Nature Communications
Simonetta M Leto, Francesco Sassi, Irene Catalano, Valter Torri, Giorgia Migliardi, Eugenia R Zanella, Mark Throsby, Andrea Bertotti, Livio Trusolino
PURPOSE: Preclinical studies in HER2-amplified gastrointestinal cancer models have shown that cotargeting HER2 with a monoclonal antibody and a small molecule is superior to monotherapy with either inhibitor, but the underlying cooperative mechanisms remain unexplored. We investigated the molecular underpinnings of this synergy to identify key vulnerabilities susceptible to alternative therapeutic opportunities. EXPERIMENTAL DESIGN: The phosphorylation/activation of HER2, HER3, EGFR (HER receptors), and downstream transducers was evaluated in HER2-overexpressing colorectal and gastric cancer cell lines by Western blotting and/or multiplex phosphoproteomics...
December 15, 2015: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Shyam M Kavuri, Naveen Jain, Francesco Galimi, Francesca Cottino, Simonetta M Leto, Giorgia Migliardi, Adam C Searleman, Wei Shen, John Monsey, Livio Trusolino, Samuel A Jacobs, Andrea Bertotti, Ron Bose
UNLABELLED: The Cancer Genome Atlas project identified HER2 somatic mutations and gene amplification in 7% of patients with colorectal cancer. Introduction of the HER2 mutations S310F, L755S, V777L, V842I, and L866M into colon epithelial cells increased signaling pathways and anchorage-independent cell growth, indicating that they are activating mutations. Introduction of these HER2 activating mutations into colorectal cancer cell lines produced resistance to cetuximab and panitumumab by sustaining MAPK phosphorylation...
August 2015: Cancer Discovery
Andrea Bertotti, Francesco Sassi
Monoclonal antibodies targeting the EGF receptor (EGFR) tyrosine kinase, such as cetuximab and panitumumab, achieve clinically meaningful responses in patients affected by head and neck and colorectal cancers. Despite this evidence of efficacy, no genomic abnormalities that robustly predict sensitivity to EGFR blockade have been yet identified. This suggests that, in some tumor contexts, EGFR dependency is not acquired during neoplastic transformation and rather reflects an aberrant declination of physiologic traits typical of normal tissue counterparts...
August 1, 2015: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Eugenia R Zanella, Francesco Galimi, Francesco Sassi, Giorgia Migliardi, Francesca Cottino, Simonetta M Leto, Barbara Lupo, Jessica Erriquez, Claudio Isella, Paolo M Comoglio, Enzo Medico, Sabine Tejpar, Eva Budinská, Livio Trusolino, Andrea Bertotti
Among patients with colorectal cancer who benefit from therapy targeted to the epidermal growth factor receptor (EGFR), stable disease (SD) occurs more frequently than massive regressions. Exploring the mechanisms of this incomplete sensitivity to devise more efficacious treatments will likely improve patients' outcomes. We tested therapies tailored around hypothesis-generating molecular features in patient-derived xenografts ("xenopatients"), which originated from 125 independent samples that did not harbor established resistance-conferring mutations...
January 28, 2015: Science Translational Medicine
Paolo Luraghi, Gigliola Reato, Elia Cipriano, Francesco Sassi, Francesca Orzan, Viola Bigatto, Francesca De Bacco, Elena Menietti, May Han, William M Rideout, Timothy Perera, Andrea Bertotti, Livio Trusolino, Paolo M Comoglio, Carla Boccaccio
Metastatic colorectal cancer remains largely incurable, although in a subset of patients, survival is prolonged by new targeting agents such as anti-EGF receptor (anti-EGFR) antibodies. This disease is believed to be supported by a subpopulation of stem-like cells termed colon cancer-initiating cell (CCIC), which may also confer therapeutic resistance. However, how CCICs respond to EGFR inhibition has not been fully characterized. To explore this question, we systematically generated CCICs through spheroid cultures of patient-derived xenografts of metastatic colorectal cancer...
March 15, 2014: Cancer Research
Alberto Bardelli, Simona Corso, Andrea Bertotti, Sebastijan Hobor, Emanuele Valtorta, Giulia Siravegna, Andrea Sartore-Bianchi, Elisa Scala, Andrea Cassingena, Davide Zecchin, Maria Apicella, Giorgia Migliardi, Francesco Galimi, Calogero Lauricella, Carlo Zanon, Timothy Perera, Silvio Veronese, Giorgio Corti, Alessio Amatu, Marcello Gambacorta, Luis A Diaz, Mark Sausen, Victor E Velculescu, Paolo Comoglio, Livio Trusolino, Federica Di Nicolantonio, Silvia Giordano, Salvatore Siena
EGF receptor (EGFR)-targeted monoclonal antibodies are effective in a subset of metastatic colorectal cancers. Inevitably, all patients develop resistance, which occurs through emergence of KRAS mutations in approximately 50% of the cases. We show that amplification of the MET proto-oncogene is associated with acquired resistance in tumors that do not develop KRAS mutations during anti-EGFR therapy. Amplification of the MET locus was present in circulating tumor DNA before relapse was clinically evident. Functional studies show that MET activation confers resistance to anti-EGFR therapy both in vitro and in vivo...
June 2013: Cancer Discovery
Andrea Bertotti, Giorgia Migliardi, Francesco Galimi, Francesco Sassi, Davide Torti, Claudio Isella, Davide Corà, Federica Di Nicolantonio, Michela Buscarino, Consalvo Petti, Dario Ribero, Nadia Russolillo, Andrea Muratore, Paolo Massucco, Alberto Pisacane, Luca Molinaro, Emanuele Valtorta, Andrea Sartore-Bianchi, Mauro Risio, Lorenzo Capussotti, Marcello Gambacorta, Salvatore Siena, Enzo Medico, Anna Sapino, Silvia Marsoni, Paolo M Comoglio, Alberto Bardelli, Livio Trusolino
UNLABELLED: Only a fraction of patients with metastatic colorectal cancer receive clinical benefit from therapy with anti-epidermal growth factor receptor (EGFR) antibodies, which calls for the identification of novel biomarkers for better personalized medicine. We produced large xenograft cohorts from 85 patient-derived, genetically characterized metastatic colorectal cancer samples ("xenopatients") to discover novel determinants of therapeutic response and new oncoprotein targets. Serially passaged tumors retained the morphologic and genomic features of their original counterparts...
November 2011: Cancer Discovery
Fortunato Ciardiello, Nicola Normanno
Primary and acquired resistance to anti-epidermal growth factor receptor (EGFR) drugs are clinically relevant problems in patients with metastatic colorectal carcinoma. A complex network of molecular alterations is involved in this phenomenon. Bertotti et al. report the development of serially transplantable groups of tumor xenografts in immune-deficient mice from patient-derived, genetically characterized metastatic colorectal carcinoma samples. These experimental models ("xenopatients") might represent a novel approach to discover and characterize the mechanisms of resistance to anti-EGFR therapy and other molecularly targeted therapies in metastatic colorectal carcinoma...
November 2011: Cancer Discovery
Giorgia Migliardi, Francesco Sassi, Davide Torti, Francesco Galimi, Eugenia R Zanella, Michela Buscarino, Dario Ribero, Andrea Muratore, Paolo Massucco, Alberto Pisacane, Mauro Risio, Lorenzo Capussotti, Silvia Marsoni, Federica Di Nicolantonio, Alberto Bardelli, Paolo M Comoglio, Livio Trusolino, Andrea Bertotti
PURPOSE: Gene mutations along the Ras pathway (KRAS, NRAS, BRAF, PIK3CA) occur in approximately 50% of colorectal cancers (CRC) and correlate with poor response to anti-EGF receptor (EGFR) therapies. We assessed the effects of mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK) and phosphoinositide 3-kinase (PI3K)/mTOR inhibitors, which neutralize the major Ras effectors, in patient-derived xenografts from RAS/RAF/PIK3CA-mutant metastatic CRCs (mCRC)...
May 1, 2012: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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