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Unresponsiveness of Colon Cancer to BRAF(V600E) Inhibition Through Feedback Activation of EGFR

20 Mar 2012
Gastrointestinal cancers
Matthias Preusser

Activating mutations of the serine threonine kinase v-RAF murine sarcoma viral oncogene homologue B1 (BRAF), most commonly of the V600E type, are found in a wide range of human neoplasms. The small molecule inhibitors of BRAF vemurafenib and dabrafenib have shown compelling clinical activity in BRAF V600E mutated metastatic melanoma. BRAF inhibition may offer a novel therapeutic opportunity in other tumour types that carry the mutation.

Approximately 10% of colorectal cancer cases show the BRAF V600E mutation. However, recent studies have documented resistance of most colon cancers to BRAF inhibition despite the presence of BRAF V600E mutation. Prahallad et al. investigated the molecular mechanisms of the intrinsic resistance of BRAF V600E mutated colorectal cancers to vemurafenib. They found that BRAF inhibition leads to rapid activation of epithelial growth factor receptor (EGFR) by inhibiting a negative feedback loop that usually inactivates EGFR. EGFR in turn activates RAS, which stimulates the formation of RAF protein dimers, against which vemurafenib is ineffective.

In addition, other proneoplastic pathways such as the PI3K/AKT pathway are activated by EGFR. In line with this concept, Prahallad et al could show that the combination of vemurafenib and the EGFR-blocking antibody cetuximab was significantly more effective in mice bearing BRAF V600E mutated colorectal cancer than each of the drugs alone. In sum, the results from this study provide a strong rationale for combined BRAF and EGFR inhibition for the treatment of BRAF V600E mutated colorectal cancers that will hopefully be explored in further studies including clinical trials.

Last update: 20 Mar 2012

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