KRAS Mutations Predict Cetuximab Resistance in Colorectal Cancer

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(ChemotherapyAdvisor) – KRAS mutations are drivers of cetuximab resistances in colorectal cancer, according to a multinational team of researchers. This conclusion is based on a paper entitled “Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer,” which was published in Nature on June 13.

The investigators aimed to identify the mechanism(s) underlying secondary resistance to therapies that selectively target kinase signaling pathways, including cetuximab, a monoclonal antibody that targets epidermal growth factor receptor (EGFR) and is effective in a subset of KRAS wild-type metastatic colorectal cancers. “After an initial response, secondary resistance invariably ensues, thereby limiting the clinical benefit of this drug. The molecular bases of secondary resistance to cetuximab in colorectal cancer are poorly understood,” the investigators wrote.

In this study, the investigators reported an association between mutations in the KRAS gene and the onset of acquired resistance to anti-EGFR treatment in colorectal cancers. Using a battery of molecular biological approaches, the investigators showed that expression of mutant KRAS was sufficient to confer cetuximab resistance. However, cetuximab-resistant cells remained sensitive to combinatorial inhibition of EGFR and mitogen-activated protein-kinase kinase (MEK), the investigators reported. Furthermore, it was reported that cetuximab-resistant metastases had KRAS amplification and that 60% of the cases acquired secondary KRAS mutations following treatment with cetuximab. Most importantly, KRAS mutations were detected in blood samples from cetuximab-treated patients as early as ten months before radiographic documentation of disease progression.

The investigators made several conclusions. First, KRAS mutations are frequent drivers of acquired resistance to cetuximab in colorectal cancers. Second, because these mutations can be detected noninvasively months before radiographic progression, early initiation of a MEK inhibitor is can be used as a strategy for delaying or reversing drug resistance.

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