Genetic Alterations Related to Anti-EGFR Therapeutic Response

Unmet Need:
Colorectal cancer is the third most common cancer worldwide, with 1.2 million patients diagnosed annually. In late-stage colorectal cancer, the most commonly used targeted therapies are monoclonal antibodies, which prevent epidermal growth factor receptor (EGFR) activation. Several studies have identified alterations in KRAS and other genes as likely mechanisms of primary and secondary resistance to anti-EGFR antibody therapy. Despite these efforts, additional mechanisms of resistance to EGFR blockade are thought to be present in colorectal cancer and little is known about determinants of sensitivity to this therapy.

Technology Overview:
Johns Hopkins researchers examined the effect of somatic genetic changes in colorectal cancer on sensitivity to a common targeted therapy, by performing complete exome sequence and copy number analyses of 129 tumors that were KRAS wild-type and analyzed their response to anti-EGFR antibody blockade in patient-derived tumorgraft models and 55 patient tumors. The genomic analyses identified novel candidate mechanisms of primary and secondary resistance through alterations affecting EGFR, its downstream signaling pathway, and other cell surface receptors, as well as all previously known mechanisms of resistance in CRC.

Stage of Development:
The inventors evaluated the role of the novel alterations identified by performing functional assays in a cetuximab-sensitive CRC cell line. They performed a proof-of-principle trials with the tumorgrafts for targeted therapies and evaluated the signaling consequences of these therapies in vivo. They found that drug combinations compared with single agents were suppresses tumor growth substantially better.

Publications:
Nature. 2015 Oct 8;526(7572):263-7.

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