(ChemotherapyAdvisor) – Rare mutations drive development of secondary skin cancers in melanoma patients taking vemurafenib, thus prompting the need for screening, according to an international team of researchers. This conclusion is based on a study entitled “The intermediate-activity L597VBRAF mutant acts as an epistatic modifier of oncogenic RAS by enhancing signaling through the RAF/MEK/ERK pathway,” which was published online in Genes & Development on August 14.
Screening for cancer-associated mutations prior to chemotherapy has become commonplace in today’s atmosphere of personalized medicine and companion diagnostics. No exception is being made for melanoma and other skin cancers, which are also driven by specific gene mutations.
In this study, the investigators aimed to determine whether mutations driving skin cancer have an impact on the patients’ response to the drug vemurafenib, and whether, based on this response, patients with melanoma should be screened prior to treatment with the drug.
Mutations in the BRAF gene have been associated with development of skin cancers and often coincide with mutations in RAS. Vemurafenib targets a mutation in BRAF, called V600E, by inhibiting BRAF from powering cancer growth. According to the investigators, this mutation is rare in melanoma patients.
Using a mouse model, the investigators observed that the rare BRAF mutation was not an independent factor in driving the development of skin cancer. However, when this mutation coincided with a specific RAS mutation, the mice developed cancers.
Based on these findings, the investigators concluded that the tumorigenic synergy between these BRAF and RAS mutations could explain the poor response to vemurafenib in some melanoma patients who go on to develop secondary skin cancers.