Evidence map›Paper›PMID 25673820›Full record

ArticleMolecular cancer therapeutics2015

Dual PI3K/mTOR Inhibitors Induce Rapid Overactivation of the MEK/ERK Pathway in Human Pancreatic Cancer Cells through Suppression of mTORC2.

Heloisa P Soares, Ming Ming, Michelle Mellon, Steven H Young, Liang Han, James Sinnet-Smith, Enrique Rozengurt

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular cancer therapeutics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers.

0numbers the graph read from it
0cells of the map it votes in
61citing papers in PubMed
5.9field-weighted citation impact, top 3% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

61 citing papers in PubMed, 95 citations in OpenAlex.

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1 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

7 authors at 1 institution in 1 country.

Heloisa P SoaresDivision of Hematology-Oncology, David Geffen School of Medicine, Los Angeles, California.
Ming MingDivision of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, Los Angeles, California.
Michelle MellonDivision of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, Los Angeles, California.
Steven H YoungDivision of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, Los Angeles, California. CURE: Digestive Diseases Research Center, University of California at Los Angeles, Los Angeles, California.
Liang HanDivision of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, Los Angeles, California.
James Sinnet-SmithDivision of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, Los Angeles, California. CURE: Digestive Diseases Research Center, University of California at Los Angeles, Los Angeles, California.
Enrique RozengurtDivision of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, Los Angeles, California. CURE: Digestive Diseases Research Center, University of California at Los Angeles, Los Angeles, California. Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California. erozengurt@mednet.ucla.edu.
University of California, Los Angeles · US

Funding

Pilot and Feasibility ProgramP30DK041301 · NIDDK · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI ROZENGURT, JUAN ENRIQUE · 1990 to 2019
$18.0M
Targeting diet-induced promotion of Kras-initiated pancreatic adenocarcinomaP01CA163200 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI PANDOL, STEPHEN J. · 2012 to 2016
$6.2M
PKD1 Signaling and Crosstalk Mechanisms in Intestinal Epithelial Cell RegulationR01DK100405 · NIDDK · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI ROZENGURT, JUAN ENRIQUE · 2014 to 2017
$1.3M
Calcium-sensing receptor signaling in the regulation of colonic epithelial cellsI01BX001473 · VA · VA GREATER LOS ANGELES HEALTHCARE SYSTEM · PI ROZENGURT, JUAN ENRIQUE · 2012 to 2015
–
BLRD VA I01 BX001473NCI NIH HHS P01 CA163200NCI NIH HHS P01CA163200NIDDK NIH HHS P30 DK041301NIDDK NIH HHS P30DK41301NIDDK NIH HHS R01 DK100405NIDDK NIH HHS R01DK100405
6 · The paper itself

Abstract

The PI3K/AKT/mTOR pathway, which is aberrantly stimulated in many cancer cells, has emerged as a target for therapy. However, mTORC1/S6K also mediates negative feedback loops that attenuate upstream signaling. Suppression of these feedback loops opposes the growth-suppressive effects of mTOR inhibitors and leads to drug resistance. Here, we demonstrate that treatment of PANC-1 or MiaPaCa-2 pancreatic ductal adenocarcinoma (PDAC) cells with the dual PI3K/mTOR kinase inhibitor (PI3K/TOR-KI) BEZ235 blocked mTORC1/S6K activation (scored by S6 phosphorylation at Ser(240/244)), mTORC1/4E-BP1 (assayed by 4E-BP1 phosphorylation at Thr(37/46)), and mTORC2-mediated AKT phosphorylation at Ser(473), in a concentration-dependent manner. Strikingly, BEZ235 markedly enhanced the MEK/ERK pathway in a dose-dependent manner. Maximal ERK overactivation coincided with complete inhibition of phosphorylation of AKT and 4E-BP1. ERK overactivation was induced by other PI3K/TOR-KIs, including PKI-587 and GDC-0980. The MEK inhibitors U126 or PD0325901 prevented ERK overactivation induced by PI3K/TOR-KIs. The combination of BEZ235 and PD0325901 caused a more pronounced inhibition of cell growth than that produced by each inhibitor individually. Mechanistic studies assessing PI3K activity in single PDAC cells indicate that PI3K/TOR-KIs act through a PI3K-independent pathway. Doses of PI3K/TOR-KIs that enhanced MEK/ERK activation coincided with those that inhibited mTORC2-mediated AKT phosphorylation on Ser(473), suggesting a role of mTORC2. Knockdown of RICTOR via transfection of siRNA markedly attenuated the enhancing effect of BEZ235 on ERK phosphorylation. We propose that dual PI3K/mTOR inhibitors suppress a novel negative feedback loop mediated by mTORC2, thereby leading to enhanced MEK/ERK pathway activity in pancreatic cancer cells.

Indexed as

Phosphoinositide-3 Kinase InhibitorsBridged Bicyclo Compounds, HeterocyclicCarrier ProteinsCell Line, TumorCell ProliferationDrug SynergismErbB ReceptorsGene Knockdown TechniquesHumansImidazolesMAP Kinase Signaling SystemMechanistic Target of Rapamycin Complex 2MorpholinesMultiprotein ComplexesPancreatic NeoplasmsProtein Kinase Inhibitors1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno(3,2-d)pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-oneBridged Bicyclo Compounds, HeterocyclicCarrier ProteinsdactolisibErbB ReceptorsgedatolisibIGF1R protein, humanImidazolesMechanistic Target of Rapamycin Complex 2MorpholinesMultiprotein ComplexesPhosphoinositide-3 Kinase InhibitorsProtein Kinase InhibitorsProto-Oncogene Proteins c-aktPyrimidinesQuinolinesRapamycin-Insensitive Companion of mTOR ProteinReceptor, IGF Type 1Receptor, InsulinReceptors, SomatomedinRICTOR protein, humanTOR Serine-Threonine KinasesTriazines

Identifiers

PMID25673820
PMCPMC4394038
OpenAlexW2165864070

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.