Evidence map›Paper›PMID 24699302›Full record

ArticleLeukemia2014

Feedbacks and adaptive capabilities of the PI3K/Akt/mTOR axis in acute myeloid leukemia revealed by pathway selective inhibition and phosphoproteome analysis.

J Bertacchini, M Guida, B Accordi, L Mediani, A M Martelli, P Barozzi, E Petricoin, L Liotta, G Milani, M Giordan and 6 more

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In one paragraph

Article in Leukemia, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.

0numbers the graph read from it
0cells of the map it votes in
40citing papers in PubMed
3.8field-weighted citation impact, top 6% 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

40 citing papers in PubMed, 70 citations in OpenAlex.

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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

16 authors at 4 institutions in 2 countries.

J Bertacchini1] Department of Surgery, Medicine, Dentistry and Morphology, University of Modena and Reggio Emilia, Modena, Italy [2] Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
M GuidaDepartment of Surgery, Medicine, Dentistry and Morphology, University of Modena and Reggio Emilia, Modena, Italy.
B AccordiDepartment of Woman's and Child's Health, University of Padova, Padova, Italy.
L MedianiDepartment of Surgery, Medicine, Dentistry and Morphology, University of Modena and Reggio Emilia, Modena, Italy.
A M MartelliDepartment of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
P BarozziSection of Hematology, Department of Medical and Surgical Science, University of Modena and Reggio Emilia, Modena, Italy.
E PetricoinCenter for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA.
L LiottaCenter for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA.
G MilaniDepartment of Woman's and Child's Health, University of Padova, Padova, Italy.
M GiordanDepartment of Woman's and Child's Health, University of Padova, Padova, Italy.
M LuppiSection of Hematology, Department of Medical and Surgical Science, University of Modena and Reggio Emilia, Modena, Italy.
F ForghieriSection of Hematology, Department of Medical and Surgical Science, University of Modena and Reggio Emilia, Modena, Italy.
A De PolDepartment of Surgery, Medicine, Dentistry and Morphology, University of Modena and Reggio Emilia, Modena, Italy.
L CoccoDepartment of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
G BassoDepartment of Woman's and Child's Health, University of Padova, Padova, Italy.
S MarmiroliDepartment of Surgery, Medicine, Dentistry and Morphology, University of Modena and Reggio Emilia, Modena, Italy.
University of Modena and Reggio Emilia · ITUniversity of Padua · ITUniversity of Bologna · ITGeorge Mason University · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Acute myeloid leukemia (AML) primary cells express high levels of phosphorylated Akt, a master regulator of cellular functions regarded as a promising drug target. By means of reverse phase protein arrays, we examined the response of 80 samples of primary cells from AML patients to selective inhibitors of the phosphatidylinositol 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) axis. We confirm that >60% of the samples analyzed are characterized by high pathway phosphorylation. Unexpectedly, however, we show here that targeting Akt and mTOR with the specific inhibitors Akti 1/2 and Torin1, alone or in combination, result in paradoxical Akt phosphorylation and activation of downstream signaling in 70% of the samples. Indeed, we demonstrate that cropping Akt or mTOR activity can stabilize the Akt/mTOR downstream effectors Forkhead box O and insulin receptor substrate-1, which in turn potentiate signaling through upregulation of the expression/phosphorylation of selected growth factor receptor tyrosine kinases (RTKs). Activation of RTKs in turn reactivates PI3K and downstream signaling, thus overruling the action of the drugs. We finally demonstrate that dual inhibition of Akt and RTKs displays strong synergistic cytotoxic effects in AML cells and downmodulates Akt signaling to a much greater extent than either drug alone, and should therefore be explored in AML clinical setting.

Indexed as

AdultAgedAged, 80 and overAntineoplastic AgentsApoptosisBenzothiazolesDrug SynergismFeedback, PhysiologicalHumansIndolesLeukemia, Myeloid, AcuteMiddle AgedPhenylurea CompoundsPhosphatidylinositol 3-KinasesPhosphorylationProteomeAKT1 protein, humanAKT2 protein, humanAntineoplastic AgentsBenzothiazolesIndolesMTOR protein, humanPhenylurea CompoundsPhosphatidylinositol 3-KinasesProteomeProto-Oncogene Proteins c-aktPyrrolesquizartinibSunitinibTOR Serine-Threonine Kinases

Identifiers

PMID24699302
OpenAlexW2034847306

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

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.