Evidence map›Paper›PMID 23542178›Full record

ArticleOncogene2014

Incomplete inhibition of phosphorylation of 4E-BP1 as a mechanism of primary resistance to ATP-competitive mTOR inhibitors.

G S Ducker, C E Atreya, J P Simko, Y K Hom, M R Matli, C H Benes, B Hann, E K Nakakura, E K Bergsland, D B Donner and 3 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Oncogene, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
59citing papers in PubMed, 1 pooled it
–field-weighted citation impact
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

59 citing papers in PubMed, 1 synthesis or guideline pooled it.

  1. Pooled it
  2. Trial
  3. Article
  4. Article
  5. The Bi-steric Inhibitor RMC-5552 Reduces mTORC1 Signaling and Growth in Lymphangioleiomyomatosis.American journal of respiratory cell and molecular biology · 2025
    Article
  6. Review
  7. Article
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  9. Lost in translation: a neglected mTOR target for lymphangioleiomyomatosis.European respiratory review : an official journal of the European Respiratory Society · 2023
    Review
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  11. Article
  12. Article
  13. Article
  14. Article
  15. Review
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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

13 authors.

G S DuckerDepartment of Chemistry, University of California, Berkeley, Berkeley, CA, USA.
C E AtreyaDepartment of Medicine, University of California, San Francisco, San Francisco, CA, USA.
J P SimkoDepartment of Pathology, University of California, San Francisco, San Francisco, CA, USA.
Y K Hom1] Preclinical Therapeutics Core, University of California, San Francisco, San Francisco, CA, USA [2] Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
M R Matli1] Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA [2] Section of Surgical Oncology, Department of Surgery, University of California, San Francisco, San Francisco, CA, USA.
C H BenesMassachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, USA.
B Hann1] Preclinical Therapeutics Core, University of California, San Francisco, San Francisco, CA, USA [2] Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
E K Nakakura1] Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA [2] Section of Surgical Oncology, Department of Surgery, University of California, San Francisco, San Francisco, CA, USA.
E K BergslandDepartment of Medicine, University of California, San Francisco, San Francisco, CA, USA.
D B Donner1] Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA [2] Section of Surgical Oncology, Department of Surgery, University of California, San Francisco, San Francisco, CA, USA.
J SettlemanMassachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, USA.
K M Shokat1] Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA [2] Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA [3] Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.
R S Warren1] Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA [2] Section of Surgical Oncology, Department of Surgery, University of California, San Francisco, San Francisco, CA, USA.

Funding

Using chemical genetics to investigate mechanisms of anesthetic actionR01EB001987 · NIBIB · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI SHOKAT, KEVAN M. · 2003 to 2012
$2.9M
Howard Hughes Medical InstituteNIBIB NIH HHS R01 EB001987
6 · The paper itself

Abstract

The mammalian target of rapamycin (mTOR) regulates cell growth by integrating nutrient and growth factor signaling and is strongly implicated in cancer. But mTOR is not an oncogene, and which tumors will be resistant or sensitive to new adenosine triphosphate (ATP) competitive mTOR inhibitors now in clinical trials remains unknown. We screened a panel of over 600 human cancer cell lines to identify markers of resistance and sensitivity to the mTOR inhibitor PP242. RAS and phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) mutations were the most significant genetic markers for resistance and sensitivity to PP242, respectively; colon origin was the most significant marker for resistance based on tissue type. Among colon cancer cell lines, those with KRAS mutations were most resistant to PP242, whereas those without KRAS mutations most sensitive. Surprisingly, cell lines with co-mutation of PIK3CA and KRAS had intermediate sensitivity. Immunoblot analysis of the signaling targets downstream of mTOR revealed that the degree of cellular growth inhibition induced by PP242 was correlated with inhibition of phosphorylation of the translational repressor eIF4E-binding protein 1 (4E-BP1), but not ribosomal protein S6 (rpS6). In a tumor growth inhibition trial of PP242 in patient-derived colon cancer xenografts, resistance to PP242-induced inhibition of 4E-BP1 phosphorylation and xenograft growth was again observed in KRAS mutant tumors without PIK3CA co-mutation, compared with KRAS wild-type controls. We show that, in the absence of PIK3CA co-mutation, KRAS mutations are associated with resistance to PP242 and that this is specifically linked to changes in the level of phosphorylation of 4E-BP1.

Indexed as

Adaptor Proteins, Signal TransducingAdenosine TriphosphateAnimalsAntineoplastic AgentsBinding, CompetitiveCarrier ProteinsCell Cycle ProteinsCell Line, TumorClass I Phosphatidylinositol 3-KinasesColonic NeoplasmsDrug Resistance, NeoplasmEukaryotic Initiation FactorsFemaleHumansIndolesMAP Kinase Signaling SystemAdaptor Proteins, Signal TransducingAdenosine TriphosphateAntineoplastic AgentsCarrier ProteinsCell Cycle ProteinsClass I Phosphatidylinositol 3-KinasesEif4ebp1 protein, mouseEukaryotic Initiation FactorsIndolesKRAS protein, humanPhosphatidylinositol 3-KinasesPhosphoproteinsPIK3CA protein, humanPP242Proto-Oncogene ProteinsProto-Oncogene Proteins p21(ras)Purinesras ProteinsRibosomal Protein S6TOR Serine-Threonine Kinases

Identifiers

PMID23542178
PMCPMC3982880

What OpenQuestion holds

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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.