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.
journal_name
Cell Signaljournal_title
Cellular signallingauthors
Goltsov A,Faratian D,Langdon SP,Bown J,Goryanin I,Harrison DJdoi
10.1016/j.cellsig.2010.10.011subject
Has Abstractpub_date
2011-02-01 00:00:00pages
407-16issue
2eissn
0898-6568issn
1873-3913pii
S0898-6568(10)00298-6journal_volume
23pub_type
杂志文章abstract：:Deficits in brain function that are associated with aging and age-related diseases benefit very little from currently available therapies, suggesting a better understanding of the underlying molecular mechanisms is needed to develop improved drugs. Here, we review the literature to test the hypothesis that a break dow...
journal_title：Cellular signalling
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abstract：:Caffeine and ryanodine triggered an increase in [Ca2+]i (73 +/- 22 and 61 +/- 18 nM, respectively) in Jurkat cell populations that was independent of external Ca2+. In individual cells, caffeine and ryanodine induced Ca2+ spikes. Jurkat cell populations initially exposed to caffeine did not respond further to ryanodin...
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abstract：PURPOSE OF REVIEW:microRNAs (miRNAs) are a class of small, evolutionarily conserved, non-coding RNAs (ncRNAs) that function as inhibitors of post-transcriptional mRNA expression. They are implicated in the pathogenesis of numerous diseases, including many common kidney conditions. In this review, we focus on how miRNAs...
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journal_title：Cellular signalling
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journal_title：Cellular signalling
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journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/0898-6568(94)00059-k
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journal_title：Cellular signalling
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doi：10.1016/j.cellsig.2020.109665
更新日期：2020-08-01 00:00:00
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journal_title：Cellular signalling
pub_type： 杂志文章,评审
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更新日期：1999-04-01 00:00:00
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journal_title：Cellular signalling
pub_type： 杂志文章,评审
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更新日期：2017-07-01 00:00:00
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journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2014.05.010
更新日期：2014-09-01 00:00:00
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journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2018.05.008
更新日期：2018-09-01 00:00:00
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journal_title：Cellular signalling
pub_type： 杂志文章,评审
doi：10.1016/0898-6568(95)02034-9
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journal_title：Cellular signalling
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doi：10.1016/j.cellsig.2005.07.006
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journal_title：Cellular signalling
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journal_title：Cellular signalling
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更新日期：2021-01-01 00:00:00
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journal_title：Cellular signalling
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更新日期：2019-05-01 00:00:00
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更新日期：2006-11-01 00:00:00
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journal_title：Cellular signalling
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journal_title：Cellular signalling
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更新日期：2017-01-01 00:00:00
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journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2007.01.001
更新日期：2007-06-01 00:00:00
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journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2013.11.005
更新日期：2014-02-01 00:00:00
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journal_title：Cellular signalling
pub_type： 杂志文章
doi：10.1016/j.cellsig.2010.04.008
更新日期：2010-09-01 00:00:00
abstract：:Protein kinase C and the annexins appear to share some unusual and potentially important membrane- and calcium-binding properties. While these proteins are calcium response elements, they are not calcium-binding proteins in the formal sense; at intracellular calcium concentrations, they only bind significant amounts o...
journal_title：Cellular signalling
pub_type： 杂志文章,评审
doi：10.1016/0898-6568(93)90075-w
更新日期：1993-07-01 00:00:00
