Imperial College London
Alternate

Dr Elaina Maginn

Faculty of Medicine, Faculty of Medicine Centre

Senior Teaching Fellow
 
 
 
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Contact

 

e.maginn

 
 
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Location

 

Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Burmi:2019:10.1080/15384047.2018.1504718,
author = {Burmi, R and Maginn, E and Gabra, H and Stronach, E and Wasan, H},
doi = {10.1080/15384047.2018.1504718},
journal = {Cancer Biology and Therapy},
pages = {21--30},
title = {Combined inhibition of the PI3K/mTOR/MEK pathway induces Bim/Mcl-2-regulated apoptosis in pancreatic cancer cells},
url = {http://dx.doi.org/10.1080/15384047.2018.1504718},
volume = {20},
year = {2019}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Burmi,R
AU  - Maginn,E
AU  - Gabra,H
AU  - Stronach,E
AU  - Wasan,H
DO  - 10.1080/15384047.2018.1504718
EP  - 30
PY  - 2019///
SN  - 1555-8576
SP  - 21
TI  - Combined inhibition of the PI3K/mTOR/MEK pathway induces Bim/Mcl-2-regulated apoptosis in pancreatic cancer cells
T2  - Cancer Biology and Therapy
UR  - http://dx.doi.org/10.1080/15384047.2018.1504718
UR  - http://hdl.handle.net/10044/1/62911
VL  - 20
ER  -
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