Publication Date: 
Saturday, March 15, 2014
MET signaling in colon cancer stem-like cells blunts the therapeutic response to EGFR inhibitors.

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.
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.