Compensatory effects in the PI3K/PTEN/AKT signaling network following receptor tyrosine kinase inhibition |
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Authors: | Goltsov Alexey Faratian Dana Langdon Simon P Bown James Goryanin Igor Harrison David J |
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Affiliation: | a Centre for Research in Informatics and Systems Pathology, University of Abertay Dundee, Dundee, DD1 1HG, United Kingdomb Edinburgh Breakthrough Research Unit and Division of Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XR, United Kingdomc School of Informatics, University of Edinburgh, Edinburgh, EH8 9AB, United Kingdom |
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Abstract: | Overcoming de novo and acquired resistance to anticancer drugs that target signaling networks is a formidable challenge for drug design and effective cancer therapy. Understanding the mechanisms by which this resistance arises may offer a route to addressing the insensitivity of signaling networks to drug intervention and restore the efficacy of anticancer therapy. Extending our recent work identifying PTEN as a key regulator of Herceptin sensitivity, we present an integrated theoretical and experimental approach to study the compensatory mechanisms within the PI3K/PTEN/AKT signaling network that afford resistance to receptor tyrosine kinase (RTK) inhibition by anti-HER2 monoclonal antibodies. In a computational model representing the dynamics of the signaling network, we define a single control parameter that encapsulates the balance of activities of the enzymes involved in the PI3K/PTEN/AKT cycle. By varying this control parameter we are able to demonstrate both distinct dynamic regimes of behavior of the signaling network and the transitions between those regimes. We demonstrate resistance, sensitivity, and suppression of RTK signals by the signaling network. Through model analysis we link the sensitivity-to-resistance transition to specific compensatory mechanisms within the signaling network. We study this transition in detail theoretically by variation of activities of PTEN, PI3K, AKT enzymes, and use the results to inform experiments that perturb the signaling network using combinatorial inhibition of RTK, PTEN, and PI3K enzymes in human ovarian carcinoma cell lines. We find good alignment between theoretical predictions and experimental results. We discuss the application of the results to the challenges of hypersensitivity of the signaling network to RTK signals, suppression of drug resistance, and efficacy of drug combinations in anticancer therapy. |
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Keywords: | HER2 inhibitor Pertuzumab ERK/PI3K/PTEN/AKT signaling network Anticancer drug resistance |
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