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Genomic and Transcriptomic Determinants of Therapy Resistance and Immune Landscape Evolution during Anti-EGFR Treatment in Colorectal Cancer

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 aberr...

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Detalles Bibliográficos
Autores principales: 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, Guettler, Sebastian, von Loga, Katharina, Rao, Sheela, Watkins, David, Starling, Naureen, Chau, Ian, Sadanandam, Anguraj, Cunningham, David, Gerlinger, Marco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617392/
https://www.ncbi.nlm.nih.gov/pubmed/31287991
http://dx.doi.org/10.1016/j.ccell.2019.05.013
Descripción
Sumario: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.