Researchers at the Wistar Institute have found a new combination treatment to effectively target a previously unknown vulnerability in NRAS mutant melanoma.

NRAS mutant melanoma makes up around a quarter of melanoma cases. Its aggressive nature, coupled with its resistance to most therapy options makes prognosis for such cases unfavourable. Additionally, the development of secondary NRAS mutations represents a mechanism of acquired resistance to targeted therapies.

“NRAS is a very attractive therapeutic target but also an extremely challenging one,” lead researcher Dr Jessie Villanueva said.

“Despite years of efforts, we don’t yet have effective ways to block the activity of mutant NRAS and the picture is further complicated by the heterogeneity of resistance mechanisms.

“We have identified a novel vulnerability in NRAS-dependent melanoma and developed a combination therapy that may offer a valuable strategy to target therapy-resistant melanoma.”

Discovering new areas of vulnerability in NRAS (and other members of the RAS family) has been a priority for researchers in recent years, as the proteins have proven difficult to target directly.

Villanueva and her team found that BET proteins (a family of transcriptional regulators) are overexpressed in NRAS mutant melanoma. Additionally, BET family member BRD4 was found to be linked with poor survival rates of NRAS mutant melanoma patients. They also found it is required for cell proliferation.

The researchers trialled small molecule inhibitors of BET proteins, finding them to decrease the viability of NRAS mutant melanoma cells. The team then examined this treatment in combination with other RAS inhibitors currently in clinical trials.

Combining BET inhibitors with MEK inhibitors (used to block a signalling pathway in melanoma), caused a marked and potent effect on melanoma both in vitro and in vivo, slowing tumour growth and increasing survival in a mouse model of NRAS mutant melanoma.

The combination was found to be more effective than either of the single treatments administered alone, causing a strong inhibition of the TCF19 transcriptional regulator.

“We are confident that clinical studies of BET and MEK combination therapy could be rapidly implemented, since BET inhibitors are in advanced clinical trials and MEK inhibitors are FDA-approved for BRAF mutant melanoma patients,” Villanueva said.

Villanueva’s lab then examined the combination therapy in different models of melanoma with intrinsic and acquired therapy resistance. The therapy was shown to significantly affect tumour growth and prolonged survival in mice models with treatment-resistant melanoma.

The success of this latter part of the study confirmed the hypothesis that co-targeting BET and MEK causes strong anti-tumour effects and could provide a viable treatment route for patients who have failed all available melanoma therapies, and possibly other treatment-resistant tumour types.

Melanoma is a type of skin cancer often identified by the appearance or alteration of a mole on the skin’s surface. Rates of melanoma incidence have been rising over the past 30 years.  It is the fifth most common type of cancer in the UK, with around 13,500 new cases diagnosed each year and around 2,000 melanoma-related deaths per year. The American Cancer Society predicts that in the US around 91,270 new cases of melanoma will be diagnosed and around 9,320 melanoma-related deaths will occur in 2018.