Evidence map›Paper›PMID 31577942›Full record

ArticleCell reports2019

Synthetic Lethal Interaction of SHOC2 Depletion with MEK Inhibition in RAS-Driven Cancers.

Rita Sulahian, Jason J Kwon, Katherine H Walsh, Emma Pailler, Timothy L Bosse, Maneesha Thaker, Diego Almanza, Joshua M Dempster, Joshua Pan, Federica Piccioni and 21 more

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

Article in Cell reports, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 67 papers.

0numbers the graph read from it
0cells of the map it votes in
67citing papers in PubMed
4.1field-weighted citation impact, top 5% 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

67 citing papers in PubMed, 90 citations in OpenAlex.

  1. Review
  2. Review
  3. Article
  4. Article
  5. Article
  6. Article
  7. Pan-ERBB Inhibitors Synergize With KRAS Inhibitors in Rectal Cancer.United European gastroenterology journal · 2025
    Article
  8. Article
  9. Article
  10. Review
  11. Molecular insights into immune evasion and therapeutic paradigms in pancreatic cancer.Chinese journal of cancer research = Chung-kuo yen cheng yen chiu · 2025
    Article
  12. Article
  13. Article
  14. Review
  15. The small GTPase MRAS is a broken switch.Nature communications · 2025
    Article
  16. Review
  17. Article
  18. Review
  19. Article
  20. Article

7 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

31 authors at 5 institutions in 1 country.

Rita SulahianBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Jason J KwonBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Katherine H WalshBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Emma PaillerBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Timothy L BosseBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Maneesha ThakerBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Diego AlmanzaBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Joshua M DempsterBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Joshua PanBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Federica PiccioniBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Nancy DumontBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Alfredo GonzalezBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Jonathan RennhackBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Behnam NabetDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA.
John A BachmanLaboratory of Systems Pharmacology, Harvard Medical School, 200 Longwood Ave., Boston, MA 02115, USA.
Amy GoodaleBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Yenarae LeeBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Mukta BagulBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Rosy LiaoBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Adrija NavarroBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Tina L YuanBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Raymond W S NgBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Srivatsan RaghavanBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA.
Nathanael S GrayDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA.
Aviad TsherniakBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Francisca VazquezBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
David E RootBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Ari J FirestoneCalico Life Sciences, South San Francisco, CA 94080, USA.
Jeff SettlemanCalico Life Sciences, South San Francisco, CA 94080, USA.
William C HahnBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, MA. Electronic address: william_hahn@dfci.harvard.edu.
Andrew J AguirreBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, MA. Electronic address: andrew_aguirre@dfci.harvard.edu.
Broad Institute · USDana-Farber Cancer Institute · USEnzo Life Sciences (United States) · USHarvard University · USCenter for Systems Biology · US

Funding

Harvard Clinical and Translational Science CenterUL1TR001102 · NCATS · HARVARD MEDICAL SCHOOL · PI NADLER, LEE MARSHALL · 2013 to 2017
$106.2M
Tissue and Pathology ResourcesP50CA127003 · NCI · DANA-FARBER CANCER INST · PI BASS, ADAM JOEL · 2007 to 2023
$33.2M
StructureP01CA154303 · NCI · DANA-FARBER CANCER INST · PI JANNE, PASI A · 2012 to 2021
$17.8M
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
Systematic identification of oncogenic KRAS synthetic lethal interactionsU01CA199253 · NCI · BROAD INSTITUTE, INC. · PI HAHN, WILLIAM C. · 2015 to 2019
$3.7M
Systematic interrogation of the pancreatic cancer microenvironment in patient-derived specimensU01CA224146 · NCI · DANA-FARBER CANCER INST · PI HAHN, WILLIAM C. · 2017 to 2021
$3.0M
Functional interrogation of epigenetic vulnerabilities in KRAS-mutant pancreatic cancerK08CA218420 · NCI · DANA-FARBER CANCER INST · PI AGUIRRE, ANDREW JAMES · 2017 to 2021
$886k
The Role of E2F2 in HER2 Positive Breast CancerK00CA212221 · NCI · DANA-FARBER CANCER INST · PI RENNHACK, JONATHAN · 2018 to 2021
$366k
Elucidating the role of SHOC2 to enhance MEK inhibitor sensitivity in pancreatic cancerF32CA243290 · NCI · DANA-FARBER CANCER INST · PI KWON, JASON · 2019 to 2021
$192k
NCATS NIH HHS UL1 TR001102NCI NIH HHS F32 CA243290NCI NIH HHS K00 CA212221NCI NIH HHS K08 CA218420NCI NIH HHS P01 CA154303NCI NIH HHS P50 CA127003NCI NIH HHS U01 CA176058NCI NIH HHS U01 CA199253NCI NIH HHS U01 CA224146
6 · The paper itself

Abstract

The mitogen-activated protein kinase (MAPK) pathway is a critical effector of oncogenic RAS signaling, and MAPK pathway inhibition may be an effective combination treatment strategy. We performed genome-scale loss-of-function CRISPR-Cas9 screens in the presence of a MEK1/2 inhibitor (MEKi) in KRAS-mutant pancreatic and lung cancer cell lines and identified genes that cooperate with MEK inhibition. While we observed heterogeneity in genetic modifiers of MEKi sensitivity across cell lines, several recurrent classes of synthetic lethal vulnerabilities emerged at the pathway level. Multiple members of receptor tyrosine kinase (RTK)-RAS-MAPK pathways scored as sensitizers to MEKi. In particular, we demonstrate that knockout, suppression, or degradation of SHOC2, a positive regulator of MAPK signaling, specifically cooperated with MEK inhibition to impair proliferation in RAS-driven cancer cells. The depletion of SHOC2 disrupted survival pathways triggered by feedback RTK signaling in response to MEK inhibition. Thus, these findings nominate SHOC2 as a potential target for combination therapy.

Indexed as

A549 CellsAnimalsCell Line, TumorCell ProliferationHCT116 CellsHumansIntracellular Signaling Peptides and ProteinsMAP Kinase Signaling SystemMiceMice, HairlessMice, SCIDMitogen-Activated Protein KinasesNeoplasmsProtein Kinase Inhibitorsras ProteinsSignal TransductionIntracellular Signaling Peptides and ProteinsMitogen-Activated Protein KinasesProtein Kinase Inhibitorsras ProteinsSHOC2 protein, humanCRISPR-Cas9 screenKRASMEK inhibitorRasSHOC2synthetic lethal

Identifiers

PMID31577942
PMCPMC6918830
OpenAlexW2979273775

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.