BRAF and
MEK inhibitors have improved outcomes for patients with BRAF-mutant
melanoma, but their efficacy is limited by both intrinsic and acquired resistances. Activation of the PI3K pathway can mediate resistance to these agents, providing a strong rationale for combination
therapy in
melanoma. Here, a panel of nine low-passage human metastatic
melanoma cell lines with BRAF mutations was tested in cell proliferation and
protein expression assays for sensitivity to inhibitors of
MEK (
selumetinib) and BRAF (
vemurafenib) as single agents and in combination with inhibitors of pan-PI3K (
ZSTK474), pan-PI3K/mTOR (
BEZ235), individual PI3K
isoforms (p110α, A66; p110β,
TGX-221; p110γ,
AS-252424; p110δ,
idelalisib), or
mTORC1/2 (KU-0063794).
Selumetinib and
vemurafenib potently inhibited cell proliferation in all cell lines, especially in those that expressed low levels of phosphorylated AKT (pAKT).
ZSTK474 and
BEZ235 also inhibited cell proliferation in all cell lines and enhanced the antitumor activity of
selumetinib and
vemurafenib in the majority of lines by either interacting synergistically or additively to increase potency or by inducing cytotoxicity by significantly increasing the magnitude of cell growth inhibition. Furthermore,
ZSTK474 or
BEZ235 combined with
selumetinib to produce robust inhibition of pERK, pAKT, and pS6 expression and synergistic inhibition of NZM20
tumor growth. The inhibitors of individual PI3K
isoforms or
mTORC1/2 were less effective at inhibiting cell proliferation either as single agents or in combination with
selumetinib or
vemurafenib, although
KU-0063794 synergistically interacted with
vemurafenib and increased the magnitude of cell growth inhibition with
selumetinib or
vemurafenib in certain cell lines. Overall, these results suggest that the sensitivity of BRAF-mutant
melanoma cells to BRAF or
MEK inhibitors is at least partly mediated by activation of the PI3K pathway and can be enhanced by combined inhibition of the BRAF/
MEK and PI3K/mTOR signaling pathways.