As for other types of malignancy, colorectal cancer is not a homogeneous disease but actually comprises multiple entities that vary in natural history and molecular pathogenesis. This heterogeneity explains why molecular cancer therapeutics against individual disease driver targets have proven to be effective in only a fraction of cases. One prototypical example is provided by the anti-epidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab and panitumumab, which are approved for the treatment of metastatic colorectal cancer. In unselected patients, the extent of clinical benefit from monotherapy with either drug hovers near the threshold for statistical significance, with response rates of approximately 10% ( 3-5 ).The population of potential responders has been recently enriched thanks to a biomarker-development strategy that is driven by the plausible biological rationale that constitutive activation of signaling pathways parallel to or downstream from EGFR, such as the RAS-RAF axis, should circumvent EGFR inhibition and therefore preclude sensitivity to EGFRtargeted agents ( 6 ). Indeed, the authors of both retrospective and prospective trials have convincingly demonstrated the inefficacy of EGFR-neutralizing antibodies in metastatic colorectal cancer patients with common (codons 12 and 13) KRAS mutations ( 7-12 ).Along this line, in a number of retrospective studies investigators have provided initial evidence that rare KRAS mutations as well as NRAS , BRAF , and (possibly) PIK3CA mutations also are significantly associated with low response rates ( 13-16 ). When considering the cumulative incidence of Only a fraction of patients with metastatic colorectal cancer receive clinical benefit from therapy with anti-epidermal growth factor receptor (EGFR) antibodies, which calls for the identification of novel biomarkers for better personalized medicine. We produced large xenograft cohorts from 85 patient-derived, genetically characterized metastatic colorectal cancer samples ("xenopatients") to discover novel determinants of therapeutic response and new oncoprotein targets. Serially passaged tumors retained the morphologic and genomic features of their original counterparts. A validation trial confirmed the robustness of this approach: xenopatients responded to the anti-EGFR antibody cetuximab with rates and extents analogous to those observed in the clinic and could be prospectively stratified as responders or nonresponders on the basis of several predictive biomarkers. Genotype-response correlations indicated HER2 amplification specifically in a subset of cetuximab-resistant, KRAS/NRAS/BRAF/PIK3CA wild-type cases. Importantly, HER2 amplification was also enriched in clinically nonresponsive KRAS wild-type patients. A proof-of-concept, multiarm study in HER2-amplified xenopatients revealed that the combined inhibition of HER2 and EGFR induced overt, long-lasting tumor regression. Our results suggest promising therapeutic opportunities in cetuximab-resistant patients with metastatic colorectal ca...

EGFR targeted monoclonal antibodies are effective in a subset of metastatic colorectal tumors (mCRC). Inevitably, all patients develop resistance, which occurs through emergence of KRAS mutations in approximately 50% of the cases. We show that amplification of the MET proto-oncogene is associated with acquired resistance in patients who do not develop KRAS mutations during anti-EGFR therapy. Amplification of the MET locus was present in circulating tumor DNA before relapse was clinically evident. Functional studies demonstrate that MET activation confers resistance to anti-EGFR therapy both in vitro and in vivo. Notably, in patient-derived CRC xenografts, MET amplification correlated with resistance to EGFR blockade which could be overcome by MET kinase inhibitors. These results highlight the role of MET in mediating primary and secondary resistance to anti-EGFR therapies in CRC and encourage the use of MET inhibitors in patients displaying resistance as a result of MET amplification.