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Autophagy suppression promotes apoptotic cell death in response to inhibition of the PI3K—mTOR pathway in pancreatic adenocarcinoma

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Abstract

Targeting of pathways downstream of RAS represents a promising therapeutic strategy for pancreatic cancer, the fourth leading cause of cancer-related death in the USA, since activation of the Raf-MEK-ERK and PI3K-AKT pathways is found frequently in this disease and is associated with poor prognosis. Taking advantage of a panel of human PDAC cell lines and specific inhibitors of PI3K and/or mTOR, we systematically address the question whether dual-targeted inhibition of the PI3K and mTOR pathways offers advantages over single-targeted inhibition of PI3K in PDAC. We observe greater overall susceptibility of cell lines to dual inhibition compared to targeting PI3K alone. However, we find that dual inhibition of PI3K and mTOR induces autophagy to a greater extent than inhibition of each target alone. In agreement with this, we show that combined administration of PI3K/mTOR and autophagy inhibitors results in increased anti-tumor activity in vitro and in vivo in models of pancreatic adenocarcinoma. XL765, a PI3K/mTOR inhibitor used in our in vivo studies, is currently undergoing clinical evaluation in a variety of cancer types, while the autophagy inhibitor chloroquine is a widely used anti-malaria compound. Thus, our studies provide rationale for clinical development of combinations of these compounds for the treatment of pancreatic adenocarcinoma.

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Abbreviations

PDAC:

Pancreatic ductal adenocarcinoma

PI3K:

Phosphoinositide-3 kinase

mTOR:

Mammalian target of rapamycin

GI50:

Drug concentration inducing 50% growth inhibition

LC50:

Drug concentration inducing 50% lethality

AVO:

Acidic vesicular organelles

3-MA:

3-Methyladenine

CQ:

Chloroquine

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Acknowledgments

We thank UCSF Laboratory for Cell Analysis and Preclinical Therapeutics Cores.

Conflicts of interest

D. Aftab is an employee and a shareholder of Exelixis, Inc. and W.M. Korn received research funding from Exelixis, Inc.

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Correspondence to W. Michael Korn.

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UC Discovery Grant bio07-10664 (W.M. Korn), Exelixis, Inc. (W.M. Korn).

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Mirzoeva, O.K., Hann, B., Hom, Y.K. et al. Autophagy suppression promotes apoptotic cell death in response to inhibition of the PI3K—mTOR pathway in pancreatic adenocarcinoma. J Mol Med 89, 877–889 (2011). https://doi.org/10.1007/s00109-011-0774-y

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  • DOI: https://doi.org/10.1007/s00109-011-0774-y

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