Faculty, Staff and Student Publications

Publication Date

8-19-2025

Journal

Cell Reports Medicine

DOI

10.1016/j.xcrm.2025.102253

PMID

40713971

PubMedCentral® Posted Date

8-19-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Humans, Syndecan-1, Proto-Oncogene Proteins p21(ras), Drug Resistance, Neoplasm, Animals, Cell Line, Tumor, YAP-Signaling Proteins, Mice, Gastrointestinal Neoplasms, Adaptor Proteins, Signal Transducing, Transcription Factors, Pancreatic Neoplasms, Molecular Targeted Therapy, Mutation, KRAS inhibitor, colorectal cancer, macropinocytosis, pancreatic cancer, syndecan, therapy resistance

Published Open-Access

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