Metastatic colorectal cancer remains largely incurable, although in a subset of patients survival is prolonged by new targeting agents such as anti-EGFR antibodies. This disease is believed to be supported by a subpopulation of stem-like cells termed colon cancer-initiating cell (CC-ICs), which may also confer therapeutic resistance. However, how CC-ICs respond to EGFR inhibition has not been fully characterized. To explore this question, we systematically generated CC-ICs through spheroid cultures of patient-derived xenografts of metastatic colorectal cancer. These cultures, termed "xenospheres", were capable of long-term self-propagation in vitro and phenocopied the original patient tumors in vivo, thus operationally defining CC-ICs . Xenosphere CC-ICs retained the genetic determinants for EGFR therapeutic response in vitro and in xenografts: like the original tumors, xenospheres harboring a mutated KRAS gene were resistant to EGFR therapy, while those harboring wild-type RAS pathway genes (RASwt) were sensitive. Notably, the effects of EGFR inhibition in sensitive CC-ICs could be counteracted by cytokines secreted by cancer-associated fibroblasts. In particular, we found the MET receptor ligand HGF was especially active in supporting in vitro CC-IC proliferation and resistance to EGFR inhibition. Ectopic production of human HGF in CC-IC xenografts rendered the xenografts susceptible to MET inhibition, which sensitized the response to EGFR therapy. By showing that RASwt CC-ICs rely on both EGFR and MET signaling, our results offer a strong preclinical proof of concept for concurrent targeting of these two pathways in the clinical setting.

MET signaling in colon cancer stem-like cells blunts the therapeutic response to EGFR inhibitors.

LURAGHI, PAOLO;REATO, Gigliola;SASSI, FRANCESCO;ORZAN, FRANCESCA NOEMI;BIGATTO, VIOLA;DE BACCO, FRANCESCA;BERTOTTI, Andrea;TRUSOLINO, Livio;COMOGLIO, Paolo;BOCCACCIO, Carla
2014

Abstract

Metastatic colorectal cancer remains largely incurable, although in a subset of patients survival is prolonged by new targeting agents such as anti-EGFR antibodies. This disease is believed to be supported by a subpopulation of stem-like cells termed colon cancer-initiating cell (CC-ICs), which may also confer therapeutic resistance. However, how CC-ICs respond to EGFR inhibition has not been fully characterized. To explore this question, we systematically generated CC-ICs through spheroid cultures of patient-derived xenografts of metastatic colorectal cancer. These cultures, termed "xenospheres", were capable of long-term self-propagation in vitro and phenocopied the original patient tumors in vivo, thus operationally defining CC-ICs . Xenosphere CC-ICs retained the genetic determinants for EGFR therapeutic response in vitro and in xenografts: like the original tumors, xenospheres harboring a mutated KRAS gene were resistant to EGFR therapy, while those harboring wild-type RAS pathway genes (RASwt) were sensitive. Notably, the effects of EGFR inhibition in sensitive CC-ICs could be counteracted by cytokines secreted by cancer-associated fibroblasts. In particular, we found the MET receptor ligand HGF was especially active in supporting in vitro CC-IC proliferation and resistance to EGFR inhibition. Ectopic production of human HGF in CC-IC xenografts rendered the xenografts susceptible to MET inhibition, which sensitized the response to EGFR therapy. By showing that RASwt CC-ICs rely on both EGFR and MET signaling, our results offer a strong preclinical proof of concept for concurrent targeting of these two pathways in the clinical setting.
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http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=24448239
HGF; Targeted therapy; invasive growth; resistance; cetuximab; colorectal cancer
Luraghi P;Reato G;Cipriano E;Sassi F;Orzan F;Bigatto V;De Bacco F;Menietti E;Han M;Rideout WM;Perera T;Bertotti A;Trusolino L;Comoglio PM;Boccaccio C
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/143265
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