by ecancer reporter Janet Fricker

A molecular rationale explaining why some BRAF or MEK inhibitor-resistant melanoma patients regain sensitivity to treatments after ‘drug holidays’ is provided by a study published online in Nature.

In over half of patients with advanced melanoma activating mutations in the BRAF oncogene have been found.

Inhibition of the oncogenic BRAF protein with the small molecule inhibitor PLX4032 (vemurafenib) or its downstream effector MEK with GSK1120212 (trametinib) have shown impressive initial responses in patients with BRAF mutant melanoma, but are rarely curative due to the rapid development of resistance.

Clinical evidence has indicated that melanoma patients who have developed vemurafenib resistance can regain sensitivity to the drug after a ‘drug holiday’, suggesting reversible and adaptive transcriptional responses to the drug.

In the current study Rene Bernards and colleagues, from the Netherlands Cancer Institute, Amsterdam, investigated whether BRAF(V600E) mutant melanoma patients develop resistance to BRAF or MEK inhibitors through acquired expression of epidermal growth factor receptor (EGFR) in their tumours.

Obtaining biopsies from 16 patients treated with the MEK inhibitor trametinib, the BRAF inhibitor dabrafenib or vemurafenib, the investigators used immunohistochemistry techniques to reveal that six out of 16 post-treatment biopsies had notable EGFR expression.

In the absence of the drugs they found that proliferation of melanoma cells engineered to express EGFR decreased as the concentration of the EGFR ligand increased.

Furthermore EGFR expression was shown to result in the induction of CDK inhibitors and acidic b-galactosidase markers, both of which are known to be associated with oncogene-induced senescence.

A second line of investigation revealed that in the presence of BRAF or MEK inhibitors the greater the expression of EGFR expression the greater the tumour proliferation.

From such observations the team concluded that in the absence of BRAF or MEK inhibitors EGFR expression is disadvantageous for BRAF(V600E) melanoma cells, but confers a selective advantage in the presence of such drugs.

“Melanoma patients whose tumours acquire EGFR expression as a result of drug resistance development may be candidates to be re-treated with drug after a drug holiday,” conclude the authors.

Reference: C Sun, L Want, S Huang, et al. Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature. doi:10.1038/nature13121