ACAGT-007a, an ERK MAPK Signaling Modulator, in Combination with AKT Signaling Inhibition Induces Apoptosis in KRAS Mutant Pancreatic Cancer T3M4 and MIA-Pa-Ca-2 Cells.

Golam Iftakhar Khandakar,Teruaki Takasaki,Reiko Sugiura,Ryosuke Satoh,Kana Fujitani,Kazuto Nishio,Kazuko Sakai,Genzoh Tanabe

doi:10.3390/cells11040702

Golam Iftakhar Khandakar, Teruaki Takasaki + Show 6 more

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https://doi.org/10.3390/cells11040702

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Journal: Cells	Publication Date: Feb 17, 2022
Citations: 6	License type: CC BY 4.0

Affiliation: Kindai University

Abstract

The mitogen-activated protein kinase (MAPK)/ERK and phosphatidylinositol-3 kinase (PI3K)/AKT pathways are dysregulated in various human cancers, including pancreatic ductal adenocarcinoma (PDAC), which has a very poor prognosis due to its lack of efficient therapies. We have previously identified ACAGT-007a (GT-7), an anti-cancer compound that kills ERK-active melanoma cells by inducing ERK-dependent apoptosis. Here, we investigated the apoptosis-inducing effect of GT-7 on three PDAC cell lines and its relevance with the MAPK/ERK and PI3K/AKT signaling pathways. GT-7 induced apoptosis in PDAC cells with different KRAS mutations (MIA-Pa-Ca-2 (KRAS G12C), T3M4 (KRAS Q61H), and PANC-1 (KRAS G12D)), being T3M4 most susceptible, followed by MIA-Pa-Ca-2, and PANC-1 was most resistant to apoptosis induction by GT-7. GT-7 stimulated ERK phosphorylation in the three PDAC cells, but only T3M4 displayed ERK-activation-dependent apoptosis. Furthermore, GT-7 induced a marked down-regulation of AKT phosphorylation after a transient peak in T3M4, whereas PANC-1 displayed the strongest and most sustained AKT activation, followed by MIA-Pa-Ca-2, suggesting that sustained AKT phosphorylation as a determinant for the resistance to GT-7-mediated apoptosis. Consistently, a PI3K inhibitor, Wortmannin, abolished AKT phosphorylation and enhanced GT-7-mediated apoptosis in T3M4 and MIA-Pa-Ca-2, but not in PANC-1, which showed residual AKT phosphorylation. This is the first report that ERK stimulation alone or in combination with AKT signaling inhibition can effectively induce apoptosis in PDAC and provides a rationale for a novel concurrent targeting of the PI3K/AKT and ERK pathways.

Highlights

We demonstrated that GT-7 induced apoptosis by stimulating ERK activation in T3M4, a pancreatic ductal adenocarcinoma (PDAC) cell line harboring the KRAS Q61H mutant allele
We further showed that the difference in the AKT phosphorylation levels upon GT-7-treatment in each PDAC cell line is a key determinant for the resistance to apoptosis induction by GT-7
T3M4 cells harbor the KRAS Q61H mutation, which is found in about 5% of PDAC patients and the most prevalent mutation occurring at codon 61 of KRAS [12]

Summary

Introduction

Pancreatic adenocarcinoma (PDAC) is one of the most lethal malignancies with a poor prognosis and high mortality rate. PDAC is notorious for its characteristic resistance to conventional chemotherapeutic regimens, including gemcitabine, while other available therapeutic options are still limited. The RAS/RAF/MEK/extracellular-signal-regulated kinase (ERK) MAPK and the PI3K/AKT pathways are frequently dysregulated in various human cancers as a result of genetic alterations in their components or upstream activation of cell-surface receptors [1]. Activating point mutations of the RAS family genes (HRAS, KRAS, and NRAS)

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