Evidence map›Paper›PMID 38328238›Full record

ArticlebioRxiv : the preprint server for biology2024

Targeting the mSWI/SNF Complex in POU2F-POU2AF Transcription Factor-Driven Malignancies.

Tongchen He, Lanbo Xiao, Yuanyuan Qiao, Olaf Klingbeil, Eleanor Young, Xiaoli S Wu, Rahul Mannan, Somnath Mahapatra, Sanjana Eyunni, Jean Ching-Yi Tien and 15 more

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

Article in bioRxiv : the preprint server for biology, 2024. 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, 9 citations in OpenAlex.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

25 authors at 5 institutions in 3 countries.

Tongchen HeMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Lanbo XiaoMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Yuanyuan QiaoMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Olaf KlingbeilCold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
Eleanor YoungMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Xiaoli S WuCold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
Rahul MannanMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Somnath MahapatraMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Sanjana EyunniMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Jean Ching-Yi TienMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Xiaoju WangMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Yang ZhengMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
NamHoon KimMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Heng ZhengMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Siyu HouDepartment of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
Fengyun SuMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Stephanie J MinerMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Rohit MehraMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Xuhong CaoMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Chandrasekhar AbbineniAurigene Oncology Limited, Bangalore, India.
Susanta SamajdarAurigene Oncology Limited, Bangalore, India.
Murali RamachandraAurigene Oncology Limited, Bangalore, India.
Abhijit ParoliaMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Christopher R VakocCold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
Arul M ChinnaiyanMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.ORCID 0000-0001-9282-3415
University of Michigan · USAurigene Discovery Technologies (India) · INCold Spring Harbor Laboratory · USHoward Hughes Medical Institute · USCentral South University · CN

Funding

Tissue/InformaticsP50CA186786 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Robert Timothy Dess · 2014 to 2026
$27.6M
Exploring Precision Oncology: From Gene Fusions to lncRNAsR35CA231996 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI CHINNAIYAN, ARUL M · 2018 to 2024
$6.4M
NCI NIH HHS P50 CA186786NCI NIH HHS R35 CA231996
6 · The paper itself

Abstract

The POU2F3-POU2AF2/3 (OCA-T1/2) transcription factor complex is the master regulator of the tuft cell lineage and tuft cell-like small cell lung cancer (SCLC). Here, we found that the POU2F3 molecular subtype of SCLC (SCLC-P) exhibits an exquisite dependence on the activity of the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex. SCLC-P cell lines were sensitive to nanomolar levels of a mSWI/SNF ATPase proteolysis targeting chimera (PROTAC) degrader when compared to other molecular subtypes of SCLC. POU2F3 and its cofactors were found to interact with components of the mSWI/SNF complex. The POU2F3 transcription factor complex was evicted from chromatin upon mSWI/SNF ATPase degradation, leading to attenuation of downstream oncogenic signaling in SCLC-P cells. A novel, orally bioavailable mSWI/SNF ATPase PROTAC degrader, AU-24118, demonstrated preferential efficacy in the SCLC-P relative to the SCLC-A subtype and significantly decreased tumor growth in preclinical models. AU-24118 did not alter normal tuft cell numbers in lung or colon, nor did it exhibit toxicity in mice. B cell malignancies which displayed a dependency on the POU2F1/2 cofactor, POU2AF1 (OCA-B), were also remarkably sensitive to mSWI/SNF ATPase degradation. Mechanistically, mSWI/SNF ATPase degrader treatment in multiple myeloma cells compacted chromatin, dislodged POU2AF1 and IRF4, and decreased IRF4 signaling. In a POU2AF1-dependent, disseminated murine model of multiple myeloma, AU-24118 enhanced survival compared to pomalidomide, an approved treatment for multiple myeloma. Taken together, our studies suggest that POU2F-POU2AF-driven malignancies have an intrinsic dependence on the mSWI/SNF complex, representing a therapeutic vulnerability.

Indexed as

IRF4mSWI/SNF complexmultiple myelomaPOU2AF1/2/3POU2F3proteolysis targeting chimera (PROTAC)small cell lung cancer (SCLC)SMARCA2/4

Identifiers

PMID38328238
PMCPMC10849552
OpenAlexW4391215078

What OpenQuestion holds

Textmetadata
LicenceCC BY
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.