Regarding a possible translational impact of this study, we provide evidence that co-targeting HH-GLI (GANT61, MRT-92) and MEK5-ERK5 (XMD8-92, JWG-071, BIX02189) pathways elicits significant antitumor activity in melanoma cells, including a drastic reduction of melanoma cell proliferation and colony formation. Here, GLI1 is linked to melanoma.