| MEK + PI3K/mTOR |
Multiple |
MEK and PI3K/mTOR1,2 inhibition is synergistic in xenograft model of NRAS melanoma |
[110] |
|
| PI3K/mTOR + BRAF + MEK |
Omipalisib (GSK2126458) |
PI3K/mTOR (with dabrafenib + trametinib) |
[111] |
|
| PKC delta |
B106 |
Novel PKC delta inhibitors demonstrated activity in NRAS melanoma cell lines and triggers apoptosis (B106, most selective and potent) |
[112] |
|
| c-MET |
PHA665752 |
c-Met phosphorylation elevated in NRAS melanoma primary tumors |
[113] |
|
| RAF |
PRi |
Enhanced efficacy of combination pan-RAF inhibitor (Amgen) with MEK inhibitor (trametinib) in NRAS melanoma cell lines |
[114] |
|
| RAF |
PLX7904 |
Novel Raf inhibitors – PLX7904 showed activity in BRAF mutant melanoma with a secondary NRAS Q61 resistance mutation |
[115] |
|
| ERK |
SCH772984 |
ERK 1/2 inhibitor, SCH772984, has single agent activity in both BRAF and NRAS mutant melanoma |
[116] |
|
| Multitarget |
Amuvatinib (MP–470) |
Multitarget kinase inhibitor (activity against c-Kit, Axl, PDGFRA, Rad61) inhibited growth of NRAS (but not BRAF) mutant melanoma cell lines |
[117] |
|
| HSP90 |
XL888 |
HSP90 inhibitor XL888 downregulated Wee1, AKT, and CDK4 in NRAS mutant melanoma in vitro and in vivo
|
[118] |
|
| GRM1 + mTOR |
Riluzole |
(GRM1 – metabotropic glutamate receptor 1 inhibitor) with mTOR inhibitor slowed melanoma growth regardless of BRAF status |
[119] |
|
| MEK + TBK1 |
|
Overexpression of TBK1 (an effector of the RAS-RAL pathway) promoted invasive behavior and inhibition/depletion of TBK1 decreased invasive features, which was enhanced with a MEK inhibitor |
[120] |
|
| mTOR + Wee1 |
MK–1775 + Torin 1 |
Wee1 inhibition potentiated inhibition of mTOR in NRAS mutant leukemia and melanoma |
[121] |
|
| MEK/ERK + ROCK |
GSK269962A + trametinib |
MEK inhibitor (or ERK inhibitor) + ROCK inhibitor resulted in decreased proliferation and cell death in vitro
|
[122] |
|
| MEK + Plk1 |
JTP–74057 + BI 6727 |
Plk1 overexpressed in NRAS melanoma. MEK and Plk1 inhibition demonstrated activity in vitro and in xenograft model of NRAS melanoma (MEK inhibitor – JTP-74057 and Plk1 inhibitor – BI 6727 |
[123] |
|
| MEK |
PD325901 |
GAB2 induces angiogenesis in NRAS mutant melanoma (and is sensitive to MEK inhibition) |
[124] |
|
| Akt/NF-kB |
BI–69A11 |
BI–69A11 (inhibitor of Akt/sphingosine kinase-NF-kB) Inhibited tumor growth in a murine model of NRAS melanoma |
[125] |
|
| MEK |
Trametinib + metformin |
Combination metformin and trametinib decreased NRAS melanoma growth in vitro and in xenograft model |
[126] |
