by ecancer reporter Janet Fricker

A Dutch study, published in Nature, provides an explanation why a subset of colon cancers respond less favourably than melanomas to treatments targeting mutations that both types of cancer share.

Activating mutations in the BRAF oncogene, BRAF (V600E), are seen in around 70% of melanomas and 10% of colon cancers. PLX4032 (vemurafenib) inhibits the BRAF (V600E) oncoprotein and is known to be highly effective in the treatment of melanomas with activating BRAF (V600E) mutations, but has not been shown to work in colon cancers sharing the same mutation.

In the current study René Bernards and colleagues, from the Netherlands Cancer Institute (Amsterdam), set out to investigate causes for this discrepancy. The investigators performed an RNA-interference-based genetic screen in human cells to search for kinases whose “knockdown” synergized with BRAF (V600E) inhibition.  They found that blockade of the epidermal growth factor receptor (EGFR) showed strong synergy with BRAF (V600E) inhibition.

 The team went on to demonstrate that BRAF (V600E) inhibition caused rapid feedback activation of EGFR, a protein that supports continued proliferation in the presence of BRAF (V600E) inhibition. In contrast to colon cancers, EGFR is not expressed in melanomas and therefore not activated following PLX4032 treatment. 

The study, say the authors, suggests that BRAF (V600E) mutant colon cancers might therefore benefit from combination therapy consisting of both BRAF and EGFR inhibitors.

Furthermore, add the authors, some studies have also shown that acquired EGFR expression occurs in a subset of melanoma patients, which may provide an explanation for the clinical resistance that occurs against PLX4032 in some melanomas.

“As BRAF (V600E) mutations are also common in thyroid papillary carcinomas and

hairy-cell leukaemias, EGFR expression levels may also help guide the selection of EGFR combination therapy in these cancers,” write the authors.

Reference

A Prahallad, C Sun, S Huang, et al. Unresponsiveness of colon cancer to BRAF (V600E) inhibition through feedback activation of EGFR. Nature. Doi:10.1038/nature10868