Researchers have identified two new panRAF inhibitors that could be used to treat patients with BRAF- or NRAS-mutant melanoma, and those who have developed resistance to BRAF inhibitors.
Researchers have identified two new panRAF inhibitors that they believe may could be used to treat patients with BRAF- or NRAS-mutant melanomas, or those patients who have developed resistance to BRAF inhibitors.
These panRAF inhibitors, identified as CCT196969 and CCT241161, are also active against the SRC family kinases (SFK), which are known to play a role in BRAF-inhibitor resistance.
“Our laboratory study showed that these new drugs deliver multiple blows to cancer by hitting several cell survival routes at once,” said study author Richard Marais, director of the Cancer Research UK Manchester Institute at the University of Manchester, in a statement. “It’s a step on from the drugs that are currently available which can’t multitask in this way.”
Marais and colleagues conducted this study in an attempt to discover an effective second-line treatment for patients with BRAF-mutant melanoma who develop resistance to BRAF inhibition. To do that they designed and synthesized molecules shaped to overcome BRAF-resistance cell signaling pathways in melanoma. They tested the molecules in vitro and in vivo, and studied the compounds using drug-resistant tumors from patients grown in mice.
The researchers tested whether CCT196969 and CCT241161 inhibited BRAF-inhibitor resistant melanoma cell lines. They found that A375 cells that were exposed to PLX4720, a BRAF inhibitor, developed resistance shown by re-growth of cells after 20 days; however, there was no re-growth of cells when the A375 cells were exposed to CCT196969 and CCT241161. The researchers also found that CCT196969 and CCT241161 inhibited the growth of PLX-4720-resistant A375 xenografts in mice.
Their studies also indicated that in addition to inhibiting the growth of BRAF-mutant melanoma cells, the compounds “do not drive paradoxical activation of the MEK/ERK pathway in RAS mutant cells.”
The researchers tested the compounds in patient-derived xenografts and found that they inhibit MEK/ERK signaling in BRAF- and NRAS-mutant melanoma and block growth of melanoma cells. The compounds were effective in melanomas with both acquired and intrinsic resistance to both BRAF and BRAF/MEK inhibitors.
The compounds were well tolerated in in vivo studies with no significant adverse effects. A dose of 20 mg/kg was established as dose for both drugs and testing showed that both of the compounds are orally bioavailable. Further clinical trials testing the drugs are scheduled to begin in 2015.