ArticleCell reports. Medicine2025
Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers.
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Article in Cell reports. Medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- Acquisition of Resistance to RAS Inhibition Is Associated with the Upregulation of Macropinocytosis through Both PI3K-Dependent and -Independent Signaling.Cancer research communications · 2026Article
- Multidrug resistance in cancer: current understandings and future perspective.Molecular biomedicine · 2026Review
- Deep Learning Enabled 3D Multi-Omic Analysis Reveals Molecular Signatures of Heterogeneous Response to Chemotherapy in Pancreatic Cancer.bioRxiv : the preprint server for biology · 2026Article
- Syndecan-1-targeted therapeutic antibody impairs macropinocytosis and elicits antitumor immunity in pancreatic cancer.Cell reports. Medicine · 2026Article
Corrections and comments
- Update of
Authors and funding
30 authors.
Madelaine S TheardyDepartment of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA.
Mitsunobu TakedaDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Osaka, Japan. Electronic address: mtakeda@gesurg.med.osaka-u.ac.jp.
Alexey SorokinDepartment of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Shuaitong ChenDepartment of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA.
Zecheng YangDepartment of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA.
Xiaofei WangDepartment of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Preeti KanikarlaDepartment of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Oluwadara CokerThe University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Phuoc NguyenThe University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Yongkun WeiDepartment of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Jun YaoDepartment of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Liang YanDepartment of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Yanqing JinDepartment of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Yiming CaiThe University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Masakatsu PakuDepartment of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Osaka, Japan.
Ziheng ChenDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Kara Z LiDepartment of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Francesca CitronDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Hideo TomiharaDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Osaka, Japan.
Sisi GaoDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Angela K DeemDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Jun ZhaoDepartment of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Huamin WangDepartment of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Samir HanashThe University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA; Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Ronald A DePinhoThe University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA; Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Anirban MaitraDepartment of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA; Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Sheikh Ahmed Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Giulio F DraettaThe University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Haoqiang YingThe University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: hying@mdanderson.org.
Scott KopetzThe University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: skopetz@mdanderson.org.
Wantong YaoDepartment of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: wyao22@mdanderson.org.
Funding
Tumor Evolution and Metastasis ProgramP30CA016672 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI Fabien Delerue · 1985 to 2026
$290.8MThe RAS and P13K Pathways in Pancreatic AdenocarcinomaP01CA117969 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI DEPINHO, RONALD ANTHONY · 2006 to 2025
$41.7MProject 3: Inhibiting Oxidative Phosphorylation in Pancreatic CancerP50CA221707 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI KOPETZ, SCOTT, MAITRA, ANIRBAN · 2019 to 2023
$11.0MUniversity of Texas PDX Development and Trial CenterU54CA224065 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI MERIC-BERNSTAM, FUNDA, ROTH, JACK · 2017 to 2022
$7.7MOvercoming adaptive feedback resistance to KRAS inhibition in colorectal cancerR01CA262805 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI Ryan Bruce Corcoran, Scott Kopetz · 2022 to 2026
$3.5MTumor Heterogeneity and Acquired Resistance to EGFR InhibitionR01CA184843 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI HAMILTON, STANLEY R., KOPETZ, SCOTT · 2015 to 2019
$3.2MTargeting Acquired Resistance in KRAS Driven CancersR37CA272744 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI Wantong Yao · 2022 to 2026
$2.2MElucidating and targeting subtype-specific driver in pancreatic cancerR01CA214793 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI YING, HAOQIANG · 2019 to 2023
$1.8MWnt/?-catenin Signaling in Pancreatic OncogenesisR01CA220236 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI MAITRA, ANIRBAN · 2017 to 2023
$1.8MFunctional Proteomics by Reverse Phase Protein Array in CancerR50CA221675 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI LU, YILING · 2017 to 2021
$726kA Novel Strategy of Targeting Transmembrane Protein to Improve KRAS-targeted TherapyR21CA288804 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI YAO, WANTONG · 2024 to 2025
$404kNCI NIH HHS P01 CA117969NCI NIH HHS P30 CA016672NCI NIH HHS P50 CA221707NCI NIH HHS R01 CA184843NCI NIH HHS R01 CA214793NCI NIH HHS R01 CA220236NCI NIH HHS R01 CA262805NCI NIH HHS R21 CA288804NCI NIH HHS R37 CA272744NCI NIH HHS R50 CA221675NCI NIH HHS U54 CA224065
Abstract
The therapeutic benefit of recently developed mutant KRAS (KRAS∗) inhibitors remains limited by the rapid onset of resistance. Here, we aim to delineate mechanisms underlying acquired resistance and identify actionable targets for overcoming this clinical challenge. Previously, we identified syndecan-1 (SDC1) as a key effector for pancreatic cancer progression whose surface expression is driven by KRAS∗. By leveraging both pancreatic and colorectal cancer models, we show that surface SDC1 expression initially diminishes upon KRAS∗ inhibition but recovers in tumor cells that bypass KRAS∗ dependency. Mechanistically, we reveal that YAP1 activation drives the recovery of SDC1 surface localization to enhance macropinocytosis-mediated nutrient salvaging and activation of multiple receptor tyrosine kinases for tumor maintenance, promoting resistance to KRAS∗-targeted therapy. Overall, our study provides a strong rationale for targeting the YAP-SDC1 axis to overcome resistance to KRAS∗ inhibition, thereby revealing promising therapeutic opportunities for improving the clinical outcome of patients with KRAS∗-mutated cancers.
Indexed as
Drug Resistance, NeoplasmGastrointestinal NeoplasmsProto-Oncogene Proteins p21(ras)Syndecan-1Adaptor Proteins, Signal TransducingAnimalsCell Line, TumorHumansMiceMolecular Targeted TherapyMutationPancreatic NeoplasmsTranscription FactorsYAP-Signaling ProteinsAdaptor Proteins, Signal TransducingKRAS protein, humanProto-Oncogene Proteins p21(ras)SDC1 protein, humanSyndecan-1Transcription FactorsYAP1 protein, humanYAP-Signaling Proteinscolorectal cancerKRAS inhibitormacropinocytosispancreatic cancersyndecantherapy resistance
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