MET signaling in colon cancer stem-like cells blunts the therapeutic response to EGFR inhibitors.
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. These cultures, termed "xenospheres," were capable of long-term self-propagation in vitro and phenocopied the original patient tumors in vivo, thus operationally defining CCICs. Xenosphere CCICs 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, whereas those harboring wild-type RAS pathway genes (RAS(wt)) were sensitive. Notably, the effects of EGFR inhibition in sensitive CCICs could be counteracted by cytokines secreted by cancer-associated fibroblasts. In particular, we found that the MET receptor ligand hepatocyte growth factor (HGF) was especially active in supporting in vitro CCIC proliferation and resistance to EGFR inhibition. Ectopic production of human HGF in CCIC xenografts rendered the xenografts susceptible to MET inhibition, which sensitized the response to EGFR therapy. By showing that RAS(wt) CCICs 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.
Authors' Affiliations: Institute for Cancer Research at Candiolo (IRCC), Center for Experimental Clinical Molecular Oncology; Department of Oncology, University of Torino, Candiolo, Torino, Italy; Aveo Oncology Inc., Cambridge, Massachusetts; and Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium.
Paolo
P
Luraghi
Gigliola
G
Reato
Elia
E
Cipriano
Francesco
F
Sassi
Francesca
F
Orzan
Viola
V
Bigatto
Francesca
F
De Bacco
Elena
E
Menietti
May
M
Han
William M
WM
Rideout
Timothy
T
Perera
Andrea
A
Bertotti
Livio
L
Trusolino
Paolo M
PM
Comoglio
Carla
C
Boccaccio
D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation; D002470:Cell Survival; D000068818:Cetuximab; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D017228:Hepatocyte Growth Factor / Q000502:physiology; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D018874:Spheroids, Cellular / Q000201:enzymology; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C066855:HGF protein, human; D017228:Hepatocyte Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D000068818:Cetuximab