Evidence map›Paper›PMID 38464081›Full record

ArticlebioRxiv : the preprint server for biology2024

Development of an orally bioavailable mSWI/SNF ATPase degrader and acquired mechanisms of resistance in prostate cancer.

Tongchen He, Caleb Cheng, Yuanyuan Qiao, Hanbyul Cho, Eleanor Young, Rahul Mannan, Somnath Mahapatra, Stephanie J Miner, Yang Zheng, NamHoon Kim and 18 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, 4 citations in OpenAlex.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

28 authors at 4 institutions in 3 countries.

Tongchen HeMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Caleb ChengMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Yuanyuan QiaoMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Hanbyul ChoMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Eleanor YoungMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, 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.
Stephanie J MinerMichigan 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.
Victoria Z ZengMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Jasmine P WisniewskiMichigan 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.
Bailey JacksonMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Xuhong CaoMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Fengyun SuMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Rui WangMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Yu ChangMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Bilash KuilaAurigene Oncology Limited, Bangalore, India.
Subhendu MukherjeeAurigene Oncology Limited, Bangalore, India.
Sandeep DukareAurigene Oncology Limited, Bangalore, India.
Kiran B AithalAurigene Oncology Limited, Bangalore, India.
Samiulla D SAurigene Oncology Limited, Bangalore, India.
Chandrasekhar AbbineniAurigene Oncology Limited, Bangalore, India.
Costas A LyssiotisRogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.ORCID 0000-0001-9309-6141
Abhijit ParoliaMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Lanbo XiaoMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, 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) · INHoward Hughes Medical Institute · USCentral South University · CN

Funding

Tissue/InformaticsP50CA186786 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Ganesh S Palapattu · 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
Cellular and Molecular Biology at MichiganT32GM145470 · NIGMS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI John Chadwick Brenner · 2022 to 2026
$4.1M
NCI NIH HHS P50 CA186786NCI NIH HHS R35 CA231996NIGMS NIH HHS T32 GM145470
6 · The paper itself

Abstract

Mammalian switch/sucrose non-fermentable (mSWI/SNF) ATPase degraders have been shown to be effective in enhancer-driven cancers by functioning to impede oncogenic transcription factor chromatin accessibility. Here, we developed AU-24118, a first-in-class, orally bioavailable proteolysis targeting chimera (PROTAC) degrader of mSWI/SNF ATPases (SMARCA2 and SMARCA4) and PBRM1. AU-24118 demonstrated tumor regression in a model of castration-resistant prostate cancer (CRPC) which was further enhanced with combination enzalutamide treatment, a standard of care androgen receptor (AR) antagonist used in CRPC patients. Importantly, AU-24118 exhibited favorable pharmacokinetic profiles in preclinical analyses in mice and rats, and further toxicity testing in mice showed a favorable safety profile. As acquired resistance is common with targeted cancer therapeutics, experiments were designed to explore potential mechanisms of resistance that may arise with long-term mSWI/SNF ATPase PROTAC treatment. Prostate cancer cell lines exposed to long-term treatment with high doses of a mSWI/SNF ATPase degrader developed SMARCA4 bromodomain mutations and ABCB1 overexpression as acquired mechanisms of resistance. Intriguingly, while SMARCA4 mutations provided specific resistance to mSWI/SNF degraders, ABCB1 overexpression provided broader resistance to other potent PROTAC degraders targeting bromodomain-containing protein 4 (BRD4) and AR. The ABCB1 inhibitor, zosuquidar, reversed resistance to all three PROTAC degraders tested. Combined, these findings position mSWI/SNF degraders for clinical translation for patients with enhancer-driven cancers and define strategies to overcome resistance mechanisms that may arise.

Indexed as

ABCB1mSWI/SNFproteolysis targeting chimera (PROTAC)SMARCA2 and SMARCA4

Identifiers

PMID38464081
PMCPMC10925251
OpenAlexW4392342434

What OpenQuestion holds

Textmetadata
LicenceCC BY
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.