Purpose: Patient-derived xenografts ("xenopatients") of
colorectal cancer metastases have been essential to identify genetic determinants of resistance to the anti-EGFR antibody
cetuximab and to explore new therapeutic strategies. From xenopatients, a genetically annotated collection of stem-like cultures ("xenospheres") was generated and characterized for response to targeted
therapies.Experimental Design: Xenospheres underwent exome-sequencing analysis, gene expression profile, and in vitro targeted treatments to assess genetic, biological, and pharmacologic correspondence with xenopatients, and to investigate nongenetic
biomarkers of therapeutic resistance. The outcome of EGFR family inhibition was tested in an NRG1-expressing in vivo model.Results: Xenospheres faithfully retained the genetic make-up of their matched xenopatients over in vitro and in vivo passages. Frequent and rare genetic lesions triggering primary resistance to
cetuximab through constitutive activation of the RAS signaling pathway were conserved, as well as the vulnerability to their respective targeted treatments. Xenospheres lacking such alterations (RASwt) were highly sensitive to
cetuximab, but were protected by
ligands activating the EGFR family, mostly NRG1. Upon reconstitution of NRG1 expression, xenospheres displayed increased tumorigenic potential in vivo and generated
tumors completely resistant to
cetuximab, and sensitive only to comprehensive EGFR family inhibition.Conclusions: Xenospheres are a reliable model to identify both genetic and nongenetic mechanisms of response and resistance to targeted
therapies in
colorectal cancer. In the absence of RAS pathway mutations, NRG1 and other EGFR
ligands can play a major role in conferring primary
cetuximab resistance, indicating that comprehensive inhibition of the EGFR family is required to achieve a significant therapeutic response. Clin
Cancer Res; 24(4); 807-20. ©2017 AACRSee related commentary by Napolitano and Ciardiello, p. 727.