Evidence map›Paper›PMID 38106234›Full record

ArticlebioRxiv : the preprint server for biology2023

SOS1 inhibition enhances the efficacy of and delays resistance to G12C inhibitors in lung adenocarcinoma.

Brianna R Daley, Nancy E Sealover, Erin Sheffels, Jacob M Hughes, Daniel Gerlach, Marco H Hofmann, Kaja Kostyrko, Barbara Mair, Amanda Linke, Zaria Beckley and 3 more

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

Article in bioRxiv : the preprint server for biology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–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

0 citing papers in PubMed, 6 citations in OpenAlex.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

13 authors at 3 institutions in 2 countries.

Brianna R DaleyDepartment of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814.
Nancy E SealoverDepartment of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814.
Erin SheffelsDepartment of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814.
Jacob M HughesDepartment of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814.
Daniel GerlachBoehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
Marco H HofmannBoehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
Kaja KostyrkoBoehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.ORCID 0000-0002-2842-4089
Barbara MairBoehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.ORCID 0000-0001-6982-2529
Amanda LinkeDepartment of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814.
Zaria BeckleyDepartment of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814.
Andrew FrankHenry M. Jackson Foundation for the Advancement of Military Medicine; Bethesda, MD, USA.
Clifton DalgardThe American Genome Center, Department of Anatomy, Cell Biology, and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814.ORCID 0000-0003-2025-8239
Robert L KortumDepartment of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814.ORCID 0000-0002-1634-4882
Uniformed Services University of the Health Sciences · USBoehringer Ingelheim (Austria) · ATHenry M. Jackson Foundation · US

Funding

Isoform-specific signaling as a determinant of RAS-driven oncogenesisR01CA255232 · NCI · HENRY M. JACKSON FDN FOR THE ADV MIL/MED · PI Robert Kortum · 2022 to 2026
$1.7M
Preventing Therapeutic Resistance in RAS-mutated Pediatric CancersR21CA267515 · NCI · HENRY M. JACKSON FDN FOR THE ADV MIL/MED · PI KORTUM, ROBERT · 2022 to 2024
$389k
NCI NIH HHS R01 CA255232NCI NIH HHS R21 CA267515
6 · The paper itself

Abstract

Clinical effectiveness of KRAS G12C inhibitors (G12Cis) is limited both by intrinsic and acquired resistance, necessitating the development of combination approaches. We found that targeting proximal receptor tyrosine kinase (RTK) signaling using the SOS1 inhibitor (SOS1i) BI-3406 both enhanced the potency of and delayed resistance to G12Ci treatment, but the extent of SOS1i effectiveness was modulated by both SOS2 expression and the specific mutational landscape. SOS1i enhanced the efficacy of G12Ci and limited rebound RTK/ERK signaling to overcome intrinsic/adaptive resistance, but this effect was modulated by SOS2 protein levels. Survival of drug-tolerant persister (DTP) cells within the heterogeneous tumor population and/or acquired mutations that reactivate RTK/RAS signaling can lead to outgrowth of tumor initiating cells (TICs) that drive therapeutic resistance. G12Ci drug tolerant persister cells showed a 2-3-fold enrichment of TICs, suggesting that these could be a sanctuary population of G12Ci resistant cells. SOS1i re-sensitized DTPs to G12Ci and inhibited G12C-induced TIC enrichment. Co-mutation of the tumor suppressor

Identifiers

PMID38106234
PMCPMC10723384
OpenAlexW4389560268

What OpenQuestion holds

Textmetadata
LicenceCC0
Read underepoch 390

Registered trials

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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.