Combined inhibition of the PI3K/mTOR/MEK pathway induces Bim/Mcl-2-regulated apoptosis in pancreatic cancer cells

Title: Combined inhibition of the PI3K/mTOR/MEK pathway induces Bim/Mcl-2-regulated apoptosis in pancreatic cancer cells
Authors: Burmi, R
Maginn, E
Gabra, H
Stronach, E
Wasan, H
Item Type: Journal Article
Abstract: Pancreatic ductal adenocarcinoma (PDAC) progression and chemotherapy insensitivity have been associated with aberrant PI3K/mTOR/MEK signalling. However, cell death responses activated by inhibitors of these pathways can differ – contextually varying with tumour genetic background. Here, we demonstrate that combining the dual PI3K/mTOR inhibitor PF5212384 (PF384) and MEK inhibitor PD325901 (PD901) more effectively induces apoptosis compared with either agent alone, independent of KRAS mutational status in PDAC cell lines. Additionally, a non-caspase dependent decrease in cell viability upon PF384 treatment was observed, and may be attributed to autophagy and G0/G1 cell cycle arrest. Using reverse phase protein arrays, we identify key molecular events associated with the conversion of cytostatic responses (elicited by single inhibitor treatments) into a complete cell death response when PF384 and PD901 are combined. This response was also independent of KRAS mutation, occurring in both BxPC3 (KRAS wildtype) and MIA-PaCa-2 (KRASG12C mutated) cells. In both cell lines, Bim expression increased in response to PF384/PD901 treatment (by 60% and 48%, respectively), while siRNA-mediated silencing of Bim attenuated the apoptosis induced by combination treatment. In parallel, Mcl-1 levels decreased by 36% in BxPC3, and 30% in MIA-PaCa-2 cells. This is consistent with a functional role for Mcl-1, and siRNA-mediated silencing enhanced apoptosis in PF384/PD901-treated MIA-PaCa-2 cells, whilst Mcl-1 overexpression decreased apoptosis induction by 24%. Moreover, a novel role was identified for PDCD4 loss in driving the apoptotic response to PF384/PD901 in BxPC3 and MIA-PaCa-2 cell lines. Overall, our data indicates PF384/PD901 co-treatment activates the same apoptotic mechanism in wild-type or KRAS mutant PDAC cells.
Issue Date: 1-Jan-2019
Date of Acceptance: 23-Jul-2018
URI: http://hdl.handle.net/10044/1/62911
DOI: https://dx.doi.org/10.1080/15384047.2018.1504718
ISSN: 1555-8576
Publisher: Taylor & Francis
Start Page: 21
End Page: 30
Journal / Book Title: Cancer Biology and Therapy
Volume: 20
Issue: 1
Copyright Statement: © 2018 The Author(s). Taylor & Francis Group, LLC This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
Sponsor/Funder: Imperial College Healthcare NHS Trust
Funder's Grant Number: FR340
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
pancreatic cancer
PI3K
mTOR
MEK
combination chemotherapy
Bim
Mcl-1
PDCD4
ORAL MEK INHIBITOR
PHASE-II
TUMOR-SUPPRESSOR
IN-VITRO
GENOMIC ANALYSES
DUAL INHIBITOR
SMALL-MOLECULE
CYCLE ARREST
LUNG-CANCER
OPEN-LABEL
Bim
MEK
Mcl-1
PDCD4
PI3K
combination chemotherapy
mTOR
pancreatic cancer
1112 Oncology And Carcinogenesis
Oncology & Carcinogenesis
Publication Status: Published
Open Access location: https://www.tandfonline.com/doi/full/10.1080/15384047.2018.1504718
Online Publication Date: 2018-09-27
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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