Evidence map›Paper›PMID 40789946›Full record

ArticleNature chemical biology2026

ZBTB11 depletion targets metabolic vulnerabilities in KRAS inhibitor-resistant PDAC.

Nathan L Tran, Jiewei Jiang, Min Ma, Gillian E Gadbois, Kevin C M Gulay, Alyssa L Verano, Cara R Schiavon, Elena Rebollo, Haowen Zhou, Chun-Teng Huang and 8 more

Abstract read
PubMed Publisher
In one paragraph

Article in Nature chemical biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing 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

5 citing papers in PubMed.

  1. Targeted therapeutic strategies forTranslational lung cancer research · 2026
    Review
  2. Article
  3. Melting KRAS resistance.Nature chemical biology · 2026
    Article
  4. Review
  5. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

18 authors.

Nathan L Tran *Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA.ORCID 0000-0002-7917-3945
Jiewei Jiang *Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA.ORCID 0000-0001-5497-9371
Min MaDepartment of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA.ORCID 0000-0002-3529-0330
Gillian E GadboisDepartment of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA.
Kevin C M GulayDepartment of Surgery, Division of Surgical Oncology, UCSD Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
Alyssa L VeranoDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.ORCID 0000-0003-2478-202X
Cara R SchiavonDepartment of Cell and Developmental Biology, University of California, San Diego, La Jolla, CA, USA.
Elena RebolloDepartment of Cell and Developmental Biology, University of California, San Diego, La Jolla, CA, USA.
Haowen ZhouSanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
Chun-Teng HuangSanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
Rabi MuradSanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
David A ScottSanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.ORCID 0000-0002-8668-2449
Uri ManorDepartment of Cell and Developmental Biology, University of California, San Diego, La Jolla, CA, USA.
Anne G BangDepartment of Surgery, Division of Surgical Oncology, UCSD Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
Herve TiriacDepartment of Surgery, Division of Surgical Oncology, UCSD Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
Andrew M LowyDepartment of Surgery, Division of Surgical Oncology, UCSD Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
Eric S WangCancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA. ewang@sbpdiscovery.org.ORCID 0000-0002-6250-9748
Fleur M FergusonDepartment of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA. fmferguson@ucsd.edu.ORCID 0000-0003-4091-7617

Funding

Structural BiologyP30CA030199 · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 1985 to 2025
$23.0M
NCI NIH HHS P30 CA030199NIH HHS S10 OD036254
6 · The paper itself

Abstract

Over 95% of pancreatic ductal adenocarcinomas (PDACs) harbor oncogenic mutations in KRAS. However, upon treatment with KRAS inhibitors, PDAC cells undergo rapid metabolic reprogramming toward an oxidative phosphorylation (OXPHOS)-dependent, drug-resistant state. Here, we demonstrate that this metabolic shift is associated with upregulation of the transcription factor ZBTB11 and both the metabolic state and resistance to KRAS inhibitors can be attenuated by ZBTB11 depletion. We develop molecular glue degraders of ZBTB11 and demonstrate that they reprogram the aberrant transcriptome, proteome, metabolome and bioenergetics of KRAS inhibitor-resistant PDAC, resensitizing them to KRAS inhibition. ZBTB11 degradation leverages cell-type-specific and cell-state-specific differences in gene-regulatory mechanisms controlling OXPHOS pathway transcripts to selectively target the KRAS inhibitor-resistant state in PDAC while sparing neurons derived from human induced pluripotent stem cells. Together, this work establishes ZBTB11 as a druggable vulnerability in KRAS inhibitor-resistant PDAC and provides a suite of molecular glue degrader tool compounds to investigate its function.

Indexed as

Antineoplastic AgentsCarcinoma, Pancreatic DuctalDrug Resistance, NeoplasmPancreatic NeoplasmsProto-Oncogene Proteins p21(ras)Repressor ProteinsCell Line, TumorHumansOxidative PhosphorylationAntineoplastic AgentsKRAS protein, humanProto-Oncogene Proteins p21(ras)Repressor Proteins

Identifiers

PMID40789946

What Socratic holds

Textmetadata
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 Socratic graph.