Wistar researchers have identified a novel therapeutic vulnerability in NRAS mutant melanoma and an effective strategy to address it, using a combination of two clinically relevant inhibitors, according to study results published online in EMBO Molecular Medicine.
NRAS mutant melanoma represents about 25 percent of melanoma cases. The prognosis for patients is generally poor because NRAS mutant melanoma is aggressive and resistant to most therapies. In addition, development of secondary NRAS mutations represents a mechanism of acquired resistance to targeted therapies.
Oncogenic NRAS has been deemed undrugabble; an alternative approach is to target NRAS effectors and non‐oncogene addictions. Co‐targeting MEK and BET synergistically downregulated TCF19 and restrained the growth of NRASMut melanoma tumors including tumors resistant to targeted and immunotherapies.
“NRAS is a very attractive therapeutic target but also an extremely challenging one,” said lead researcher Jessie Villanueva, Ph.D., assistant professor in the Molecular & Cellular Oncogenesis Program at Wistar. “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,” she added.
The researchers paired JQ-1 with MEK inhibitors PD0325901; PD901, PD0332991; PD991, BKM120, trametinib and BET inhibitor OTX‐015 (MK‐8628), which is currently in phase II clinical trials for solid tumors. BETi/MEKi combinations significantly increased the survival of mice that were treated for 21 days, without evidence of toxicity.
“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,” added Villanueva.
Currently approved MEK inhibitors include: Trametinib (Novartis) and Cobimetinib (Genentech)
BET inhibitors in clinical trials include: GSK525762 (GSK),OTX-015 (Merck), CPI-0610 (Constellation Pharmaceuticals)
You can find the complete study results here.