A Plastic EMP1+ to LGR5+ Cell State Conversion as a Bypass to KRASG12D Pharmacologic Inhibition in Metastatic Colorectal Cancer
Year: 2025
Type: article
Abstract: Inhibitors of the oncogene KRAS hold promise for treating metastatic colorectal cancer (mCRC). In this study, we show that a selective, covalent small-molecule inhibitor of the active (ON) conformation of RAS-G12D, RMC-9945, exerts durable disease control in preclinical colorectal cancer models of early liver metastasis, but its therapeutic activity was diminished in the advanced metastatic disease. RMC-9945-treated metastases underwent a transition from a poor prognosis-associated Emp1+ transcriptional state to a WNT-driven Lgr5+ stem cell-like state that withstands the absence of RAS-G12D activity. This cell state change occurred within hours of RAS(ON) inhibitor treatment through a shift in transcription factor usage that involved limited chromatin remodeling. Forced conversion of metastatic cells to the Lgr5+ state through RAS-G12D inhibition, followed by genetic ablation of this population, reduced metastatic burden and prolonged survival in a mouse mCRC model. Overall, these preclinical findings demonstrate a central role for oncogenic KRAS in governing cellular plasticity in mCRC. SIGNIFICANCE: We show that inhibition of oncogenic KRAS in preclinical models of advanced mCRC exerts a limited benefit, primarily due to the reversion of tumor cells to a stem cell-like state. Our findings highlight the context-dependent effects of oncogenic KRAS mutations and underscore cell plasticity as a therapeutic opportunity. See related commentary by Eng and Yilmaz et al., p. 201.
Source: Cancer Discovery
Authors: Alessia Centonze, Adrià-Jaume Roura, Meritxell Novillo-Font, Cristina Giordano, Xavier Hernando-Momblona, Montserrat Llanses, Paula Prats, Marta Sevillano, Débora Cabot, Mireia Novell, Gabriel Pabst, Florian Andersch, Adrià Cañellas-Socias, Chong Zhang, Nikolaos-Nikiforos Giakoumakis, Hugh Sparks, Chris Dunsby, Julien Colombelli, Asunción Fernández-Barral, Elena Sancho, Camille Stephan-Otto Attolini, Alberto Muñoz, Antonio Barbachano, Héctor G. Palmer, Jordi Martínez-Quintanilla, Johannes Zuber, Cristina Blaj, Elsa Quintana, Carme Cortina, Marc A. Marti-Renom, Eduard Batlle
Institutions: Institute for Research in Biomedicine, Barcelona Institute of Science and Technology, Centro de Investigación Biomédica en Red de Cáncer, Centre for Genomic Regulation, Centro Nacional de Análisis Genómico, Vall d'Hebron Institute of Oncology, Research Institute of Molecular Pathology, Vienna Biocenter, The Francis Crick Institute, Imperial College London, Consejo Superior de Investigaciones Científicas, Hospital Universitario La Paz, Instituto de Investigaciones Biomédicas Sols-Morreale, Hospital La Paz Institute for Health Research, Universidad Autónoma de Madrid, Revolution Medicines (United States), Institució Catalana de Recerca i Estudis Avançats
Language: English
Topic: Cancer Cells and Metastasis
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Funders: Institute for Research in Biomedicine, “la Caixa” Foundation, Revolution Medicines, Cancer Research UK, Fundación Científica Asociación Española Contra el Cáncer, Generalitat de Catalunya, Ministerio de Ciencia e Innovación, Centro de Investigación Biomédica en Red de Cáncer, European Research Council, H2020 European Research Council
OpenAlex ID: W4415476185