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Bertotti Colon Cancer EGFR

Paolo Luraghi, Viola Bigatto, Elia Cipriano, Gigliola Reato, Francesca Orzan, Francesco Sassi, Francesca De Bacco, Claudio Isella, Sara E Bellomo, Enzo Medico, Paolo M Comoglio, Andrea Bertotti, Livio Trusolino, Carla Boccaccio
Purpose: Patient-derived xenografts (" xenopatients ") of colorectal cancer metastases have been essential to identify genetic determinants of resistance to the anti-EGFR antibody cetuximab and to explore new therapeutic strategies. From xenopatients, a genetically annotated collection of stem-like cultures (" xenospheres ") was generated and characterized for response to targeted therapies. Experimental Design: Xenospheres underwent exome-sequencing analysis, gene expression profile, and in vitro targeted treatments to assess genetic, biological, and pharmacologic correspondence with xenopatients, and to investigate nongenetic biomarkers of therapeutic resistance...
February 15, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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...
November 1, 2016: Oncotarget
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
Chong Sun, Sebastijan Hobor, Andrea Bertotti, Davide Zecchin, Sidong Huang, Francesco Galimi, Francesca Cottino, Anirudh Prahallad, Wipawadee Grernrum, Anna Tzani, Andreas Schlicker, Lodewyk F A Wessels, Egbert F Smit, Erik Thunnissen, Pasi Halonen, Cor Lieftink, Roderick L Beijersbergen, Federica Di Nicolantonio, Alberto Bardelli, Livio Trusolino, Rene Bernards
There are no effective therapies for the ~30% of human malignancies with mutant RAS oncogenes. Using a kinome-centered synthetic lethality screen, we find that suppression of the ERBB3 receptor tyrosine kinase sensitizes KRAS mutant lung and colon cancer cells to MEK inhibitors. We show that MEK inhibition results in MYC-dependent transcriptional upregulation of ERBB3, which is responsible for intrinsic drug resistance. Drugs targeting both EGFR and ERBB2, each capable of forming heterodimers with ERBB3, can reverse unresponsiveness to MEK inhibition by decreasing inhibitory phosphorylation of the proapoptotic proteins BAD and BIM...
April 10, 2014: Cell Reports
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
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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