Evidence map›Paper›PMID 24909179›Full record

ArticleOncogene2015

PRKACA mediates resistance to HER2-targeted therapy in breast cancer cells and restores anti-apoptotic signaling.

S E Moody, A C Schinzel, S Singh, F Izzo, M R Strickland, L Luo, S R Thomas, J S Boehm, S Y Kim, Z C Wang and 1 more

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

Article in Oncogene, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 70 papers.

0numbers the graph read from it
0cells of the map it votes in
70citing papers in PubMed
6.8field-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

70 citing papers in PubMed, 116 citations in OpenAlex.

  1. Article
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  8. Therapeutic, Clinicopathological, and Molecular Correlates ofPharmaceuticals (Basel, Switzerland) · 2024
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  12. Correlation analysis of lipid metabolism genes with the immune microenvironment in gastric cancer and the construction of a novel gene signature.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2023
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10 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

11 authors at 4 institutions in 1 country.

S E Moody1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA [2] Department of Medicine, Bringham and Women's Hospital and Harvard Medical School, Boston, MA, USA [3] Broad Institute of MIT and Harvard, Cambridge, MA, USA.
A C SchinzelDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
S SinghDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
F IzzoDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
M R StricklandDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
L Luo1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA [2] Department of Medicine, Bringham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
S R ThomasBroad Institute of MIT and Harvard, Cambridge, MA, USA.
J S BoehmBroad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID 0000000267956336
S Y KimDepartment of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA.
Z C Wang1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA [2] Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
W C Hahn1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA [2] Department of Medicine, Bringham and Women's Hospital and Harvard Medical School, Boston, MA, USA [3] Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Dana-Farber Cancer Institute · USBroad Institute · USBrigham and Women's Hospital · USDuke University · US

Funding

Signatures of Kinase Activation in Cancer (MIT consortium)U54CA112962 · NCI · DANA-FARBER CANCER INSTITUTE · PI GOLUB, TODD R. · 2004 to 2014
$24.2M
The Dana-Farber Cancer Institute Cancer Target Discovery and Development CenterU01CA176058 · NCI · DANA-FARBER CANCER INST · PI HAHN, WILLIAM C. · 2013 to 2021
$7.8M
Regulation and function of IKKe in breast cancer initiation and maintenanceR01CA130988 · NCI · DANA-FARBER CANCER INST · PI HAHN, WILLIAM C. · 2009 to 2018
$3.5M
NCI NIH HHS R01 CA130988NCI NIH HHS U01 CA176058NCI NIH HHS U54 CA112962
6 · The paper itself

Abstract

Targeting HER2 with antibodies or small molecule inhibitors in HER2-positive breast cancer leads to improved survival, but resistance is a common clinical problem. To uncover novel mechanisms of resistance to anti-HER2 therapy in breast cancer, we performed a kinase open reading frame screen to identify genes that rescue HER2-amplified breast cancer cells from HER2 inhibition or suppression. In addition to multiple members of the MAPK (mitogen-activated protein kinase) and PI3K (phosphoinositide 3-kinase) signaling pathways, we discovered that expression of the survival kinases PRKACA and PIM1 rescued cells from anti-HER2 therapy. Furthermore, we observed elevated PRKACA expression in trastuzumab-resistant breast cancer samples, indicating that this pathway is activated in breast cancers that are clinically resistant to trastuzumab-containing therapy. We found that neither PRKACA nor PIM1 restored MAPK or PI3K activation after lapatinib or trastuzumab treatment, but rather inactivated the pro-apoptotic protein BAD, the BCl-2-associated death promoter, thereby permitting survival signaling through BCL-XL. Pharmacological blockade of BCL-XL/BCL-2 partially abrogated the rescue effects conferred by PRKACA and PIM1, and sensitized cells to lapatinib treatment. These observations suggest that combined targeting of HER2 and the BCL-XL/BCL-2 anti-apoptotic pathway may increase responses to anti-HER2 therapy in breast cancer and decrease the emergence of resistant disease.

Indexed as

Antibodies, Monoclonal, HumanizedAntineoplastic AgentsApoptosisbcl-Associated Death Proteinbcl-X ProteinBreast NeoplasmsCyclic AMP-Dependent Protein Kinase Catalytic SubunitsDrug Resistance, NeoplasmErb-b2 Receptor Tyrosine KinasesFemaleGene Expression ProfilingHEK293 CellsHumansLapatinibMitogen-Activated Protein KinasesOpen Reading FramesAntibodies, Monoclonal, HumanizedAntineoplastic AgentsBAD protein, humanBCL2L1 protein, humanbcl-Associated Death Proteinbcl-X ProteinCyclic AMP-Dependent Protein Kinase Catalytic SubunitsERBB2 protein, humanErb-b2 Receptor Tyrosine KinasesLapatinibMitogen-Activated Protein KinasesPhosphatidylinositol 3-KinasesPIM1 protein, humanPRKACA protein, humanProtein Kinase InhibitorsProto-Oncogene Proteins c-pim-1QuinazolinesTrastuzumab

Identifiers

PMID24909179
PMCPMC4261061
OpenAlexW1969312124

What OpenQuestion holds

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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.