Evidence map›Paper›PMID 37195712›Full record

ArticleClinical cancer research : an official journal of the American Association for Cancer Research2023

MEK Inhibition Sensitizes Pancreatic Cancer to STING Agonism by Tumor Cell-intrinsic Amplification of Type I IFN Signaling.

Razmik Ghukasyan, Keke Liang, Kevin Chau, Luyi Li, Charlotte Chan, Evan R Abt, Thuc Le, Joon Y Park, Nanping Wu, Alykhan Premji and 7 more

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

Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.

0numbers the graph read from it
0cells of the map it votes in
9citing papers in PubMed
1.3field-weighted citation impact, top 19% 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

9 citing papers in PubMed, 8 citations in OpenAlex.

  1. Article
  2. Review
  3. Review
  4. Review
  5. Review
  6. Review
  7. Review
  8. Article
  9. Article
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

17 authors at 1 institution in 2 countries.

Razmik Ghukasyan *Department of Surgery, University of California Los Angeles, Los Angeles, California.ORCID 0000-0003-1795-1892
Keke Liang *Department of Surgery, University of California Los Angeles, Los Angeles, California.ORCID 0000-0002-0007-6326
Kevin ChauDepartment of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California.ORCID 0000-0001-9945-9169
Luyi LiDepartment of Surgery, University of California Los Angeles, Los Angeles, California.ORCID 0000-0001-6096-6403
Charlotte ChanDepartment of Surgery, University of California Los Angeles, Los Angeles, California.ORCID 0000-0001-5036-7298
Evan R AbtDepartment of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California.ORCID 0000-0002-3160-7134
Thuc LeDepartment of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California.ORCID 0000-0003-2364-9374
Joon Y ParkDepartment of Surgery, University of California Los Angeles, Los Angeles, California.ORCID 0000-0002-3847-9198
Nanping WuDepartment of Surgery, University of California Los Angeles, Los Angeles, California.ORCID 0000-0001-6415-009X
Alykhan PremjiDepartment of Surgery, University of California Los Angeles, Los Angeles, California.ORCID 0000-0002-0326-3717
Robert DamoiseauxDepartment of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California.ORCID 0000-0002-7611-7534
Tony LuuDepartment of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California.ORCID 0009-0003-1014-9300
Amanda LaboraDepartment of Surgery, University of California Los Angeles, Los Angeles, California.ORCID 0000-0001-6273-0939
Khalid RashidDepartment of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California.ORCID 0000-0002-5070-8010
Jason M LinkDepartment of Surgery, University of California Los Angeles, Los Angeles, California.ORCID 0000-0002-6892-0431
Caius G RaduDavid Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.ORCID 0000-0002-9338-5397
Timothy R DonahueDepartment of Surgery, University of California Los Angeles, Los Angeles, California.ORCID 0000-0002-1175-2545
University of California, Los Angeles · US

Funding

UCLA SPORE in Brain CancerP50CA211015 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI David A. Nathanson · 2017 to 2026
$25.2M
GASTROENTEROLOGYT32DK007180 · NIDDK · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI JENSEN, DENNIS MICHAEL · 1986 to 2025
$10.0M
Leveraging Vulnerabilities Induced by STING Activation in Pancreatic CancerR01CA250529 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI DONAHUE, TIMOTHY R, RADU, CAIUS GABRIEL · 2021 to 2025
$3.1M
Targeting KRAS and adenosine mediated immunosuppression in pancreatic cancerR01CA260678 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI DONAHUE, TIMOTHY R, RADU, CAIUS GABRIEL · 2021 to 2025
$3.0M
NCI NIH HHS P50 CA211015NCI NIH HHS R01 CA250529NCI NIH HHS R01 CA260678NIDDK NIH HHS T32 DK007180
6 · The paper itself

Abstract

purposeStimulator of interferon genes (STING) agonists are currently in development for treatment of solid tumors, including pancreatic ductal adenocarcinoma (PDAC). Response rates to STING agonists alone have been promising yet modest, and combination therapies will likely be required to elicit their full potency. We sought to identify combination therapies and mechanisms that augment the tumor cell-intrinsic effect of therapeutically relevant STING agonists apart from their known effects on tumor immunity. EXPERIMENTAL

designWe screened 430 kinase inhibitors to identify synergistic effectors of tumor cell death with diABZI, an intravenously administered and systemically available STING agonist. We deciphered the mechanisms of synergy with STING agonism that cause tumor cell death in vitro and tumor regression in vivo.

resultsWe found that MEK inhibitors caused the greatest synergy with diABZI and that this effect was most pronounced in cells with high STING expression. MEK inhibition enhanced the ability of STING agonism to induce type I IFN-dependent cell death in vitro and tumor regression in vivo. We parsed NFκB-dependent and NFκB-independent mechanisms that mediate STING-driven type I IFN production and show that MEK signaling inhibits this effect by suppressing NFκB activation.

conclusionsOur results highlight the cytotoxic effects of STING agonism on PDAC cells that are independent of tumor immunity and that these therapeutic benefits of STING agonism can be synergistically enhanced by MEK inhibition.

Indexed as

Antineoplastic AgentsCarcinoma, Pancreatic DuctalInterferon Type IPancreatic NeoplasmsHumansMitogen-Activated Protein Kinase KinasesSignal TransductionAntineoplastic AgentsInterferon Type IMitogen-Activated Protein Kinase Kinases

Identifiers

PMID37195712
PMCPMC10865884
OpenAlexW4376872402

What OpenQuestion holds

Textmetadata
LicenceTDM
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.