Concomitant blockade of EGFR and MEK overcomes acquired resistance to anti-EGFR therapy in colorectal cancer cells and patients’ avatars.

Abstract

2626 Background: The anti-EGFR antibodies cetuximab and panitumumab are approved for the treatment of RAS wild-type colorectal cancer (CRC) patients. The clinical efficacy of EGFR targeted antibodies is limited by the development of acquired (secondary) resistance. Here we investigated the molecular bases of relapse to anti-EGFR blockade in CRC cells and patients' samples and use xenotransplants to define a clinically applicable strategy to overcome acquired resistance. Methods: Molecular profiling of circulating tumor DNA was used to identify the emergence of mutations in plasma samples of patients who relapsed after anti EGFR therapies. Xenografted tumors (avatars) from patients who relapsed after EGFR blockade were established and exploited to assess the efficacy of drugs aimed at bypassing acquired resistance. Results: Emergence of concomitant mutations in KRAS and NRAS was detected in samples from 5 CRC patients who developed resistance to anti-EGFR antibodies. Acquired resistance to cetuximab and pa...