Abstract
Co-inhibition of EGFR and MEK kills colorectal cancer cells with acquired EGFR antibody resistance.
Major finding: Co-inhibition of EGFR and MEK kills colorectal cancer cells with acquired EGFR antibody resistance.
Concept: Heterogeneous mutations drive EGFR antibody resistance and converge on the MEK—ERK pathway.
Impact: Adding MEK inhibitors to anti-EGFR therapy may overcome acquired resistance in colorectal cancer.
EGF receptor (EGFR)-blocking antibodies such as cetuximab and panitumumab have been used to treat a subset of RAS—wild-type colorectal cancers, yet responsiveness is transient, as tumors become resistant and progress within months. Acquired resistance to targeted therapies is difficult to overcome because relapsed tumors are highly heterogeneous. To model acquired resistance in vitro, Misale and colleagues treated a panel of RAS—wild-type colorectal cancer cell lines with cetuximab or panitumumab and found that the resistant populations that emerged harbored polyclonal activating mutations in KRAS, NRAS, or BRAF. Sustained MEK and/or ERK activation occurred in all resistant clones independently of their mutational status, and acquired anti-EGFR therapy resistance mechanisms in colorectal cancer cells converged upon the MEK—ERK pathway. However, the MEK inhibitor pimasertib did not significantly affect the growth of resistant cells, as it induced only a transient suppression of ERK activation and subsequently stimulated EGFR phosphorylation. In contrast, combined treatment with pimasertib plus cetuximab blocked EGFR phosphorylation and caused a sustained inhibition of ERK activation. Concomitant MEK and EGFR blockade also induced a long-term growth suppression of resistant cell lines in vitro and triggered a significant regression of established tumors derived from resistant cell lines in nude mice. Notably, heterogeneous KRAS, NRAS, and BRAF mutations could be detected in the blood of patients with colorectal cancer who had developed resistance to anti-EGFR antibodies, and combined pimasertib–cetuximab treatment markedly impaired tumor growth in a colorectal cancer patient–derived xenograft model. Together, these findings highlight the MEK—ERK pathway as a critical point of convergence for multiple genetic alterations that drive anti-EGFR drug resistance in colorectal cancer and provide a rationale for clinical evaluation of concomitant EGFR and MEK inhibition in patients with refractory colorectal cancer.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
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