Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease in urgent need of newer therapeutic modalities. Majority of patients with PDAC have mutations in KRAS, which unfortunately remains an ineffectual target. Our strategy here is to target KRAS downstream effectors PI3K and mTOR. In this study, we investigated the antitumor efficacy of the novel PI3K and mTOR dual inhibitor VS-5584 in PDAC. Our data shows that PI3K/mTOR dual inhibition causes ERK activation in all tested PDAC cell lines. Although the MEK inhibitor GSK1120212 could abrogate VS-5584-induced ERK activation, it did not substantially enhance cell death in all the cell lines tested. However, combination with ERK inhibitor SCH772984 not only mitigated VS-5584-induced ERK activation but also enhanced VS-5584-induced cell death. In a xenograft model of PDAC, we observed 28% and 44% tumor inhibition for individual treatment with VS-5584 and SCH772984, respectively, while the combined treatment showed superior tumor inhibition (80%) compared to vehicle control treatment. Our findings support the clinical development of VS-5584 and ERK inhibitor combination for PDAC treatment.
Highlights
Pancreatic cancer has a 5-year survival rate of only 8% in the United States [1]
We found that VS-5584 treatment causes activation of ERK and that targeting MEK, which is upstream of ERK, does not enhance VS-5584 antitumor activity in a wild-type KRAS Pancreatic ductal adenocarcinoma (PDAC) cell line
In HPAC cells, 2 μM VS-5584 caused substantial decrease of p-S6 by 4 h post-treatment, while decreased p-AKT(S473) and p-AKT(T308) were not detected until 12 h post-VS-5584 treatment (Figure 2D). Despite inhibition of both PI3K and mTOR, VS-5584 did not induce an appreciable amount of cell death (Figure 1F)
Summary
Pancreatic cancer has a 5-year survival rate of only 8% in the United States [1]. The PI3K/mTOR pathway, which is downstream of KRAS, is commonly deregulated in many cancer types [9]. Rapalogs have demonstrated limited clinical benefits due to drug-induced feedback loops, which cause hyperactivation of PI3K/AKT and enhance the proliferation rate of tumors [11, 12]. These findings have led to the development of dual PI3K and mTOR inhibitors which can overcome feedback activation of PI3K resulting from mTOR inhibition. Efficacy can be hindered by activation of other pathways
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