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Título: | Genomic and Transcriptomic Determinants of Therapy Resistance and Immune Landscape Evolution during Anti-EGFR Treatment in Colorectal Cancer |
Autor: | Woolston, Andrew; Khan, Khurum; Spain, Georgia; Barber, Louise J.; Griffiths, Beatrice; Gonzalez-Exposito, Reyes; Hornsteiner, Lisa; Punta, Marco; Patil, Yatish; Newey, Alice; Mansukhani, Sonia; Davies, Matthew N.; Furness, Andrew; Sclafani, Francesco; Peckitt, Clare; Jiménez, Mirta; Kouvelakis, Kyriakos; Ranftl, Romana; Begum, Ruwaida; Rana, Isma; Thomas, Janet; Bryant, Annette; Quezada, Sergio; Wotherspoon, Andrew; Khan, Nasir; Fotiadis, Nikolaos; Marafioti, Teresa; Powles, Thomas; Lise, Stefano; Calvo, Fernando CSIC ORCID ; Guettler, Sebastian; Von Loga, Katharina; Rao, Sheela; Watkins, David; Starling, Naureen; Chau, Ian; Sadanandam, Anguraj; Cunningham, David; Gerlinger, Marco | Palabras clave: | Cancer evolution EGFR Drug resistance mechanisms Molecular subtype Colorectal cancer Cetuximab Predictive biomarker Immunotherapy Cancer genomics Cancer-associated fibroblasts |
Fecha de publicación: | 2019 | Editor: | Elsevier | Citación: | Cancer Cell 36(1): 35-50.e9(2019) | Resumen: | Despite biomarker stratification, the anti-EGFR antibody cetuximab is only effective against a subgroup of colorectal cancers (CRCs). This genomic and transcriptomic analysis of the cetuximab resistance landscape in 35 RAS wild-type CRCs identified associations of NF1 and non-canonical RAS/RAF aberrations with primary resistance and validated transcriptomic CRC subtypes as non-genetic predictors of benefit. Sixty-four percent of biopsies with acquired resistance harbored no genetic resistance drivers. Most of these had switched from a cetuximab-sensitive transcriptomic subtype at baseline to a fibroblast- and growth factor-rich subtype at progression. Fibroblast-supernatant conferred cetuximab resistance in vitro, confirming a major role for non-genetic resistance through stromal remodeling. Cetuximab treatment increased cytotoxic immune infiltrates and PD-L1 and LAG3 immune checkpoint expression, potentially providing opportunities to treat cetuximab-resistant CRCs with immunotherapy. | Versión del editor: | http://dx.doi.org/10.1016/j.ccell.2019.05.013 | URI: | http://hdl.handle.net/10261/210130 | DOI: | 10.1016/j.ccell.2019.05.013 | ISSN: | 1535-6108 | E-ISSN: | 1878-3686 |
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