MET inhibitors challenge resistant colorectal cancer
Colorectal tumors that had developed resistance to anti-epidermal growth factor receptor (anti-EGFR) therapies responded to drugs that block the action of the MET oncogene in a recent study. The project also demonstrated that MET amplification could be detected easily in blood samples.
Although EGFR-targeted monoclonal antibodies are effective against a subset of metastatic colorectal cancers, all patients inevitably develop resistance, explained Alberto Bardelli, PhD, and colleagues in Cancer Discovery, a journal of the American Association for Cancer Research (AACR). Bardelli, an associate professor in the Department of Oncology at the University of Torino in Candiolo, Torino, Italy, and his team noted that this resistance occurs through emergence of KRAS mutations in approximately 50% of cases. This percentage jumps to about 60% when including mutations in the BRAF and NRAS genes, which, like KRAS, are related to EGFR signaling.
The investigators showed that amplification of the MET gene is associated with acquired resistance in colorectal tumors that do not develop KRAS mutations during anti-EGFR therapy.
“Our studies provide evidence that colorectal cancer resistance to anti-EGFR therapies can be driven by MET gene amplification,” affirmed Bardelli in a statement issued by the AACR.
But what he described as “more exciting” was that his group was able to detect these amplifications in the blood: After analyzing tumors from seven patients who had developed resistance subsequent to anti-EGFR therapy, Bardelli and associates identified three persons who did not have the previously known KRAS, BRAF, or NRAS mutations. Next-generation sequencing was used to demonstrate MET amplification in these three tumor samples. Blood samples collected regularly during anti-EGFR therapy until relapse were available for two of those three patients. The researchers were able to detect MET amplification in the blood, and were able to show that amplification occurred prior to relapse.
As Bardelli pointed out in the AACR statement, the ability to detect MET amplification in blood provides a noninvasive, highly sensitive method for monitoring and predicting drug resistance and tumor recurrence.Further, testing of the clinically approved MET inhibitor crizotinib in two mice carrying patient-derived, drug-resistant colorectal cancers showed that combining crizotinib with an anti-EGFR agent produced maximum antitumor activity and sustained response in both mice.