A Plastic EMP1+ to LGR5+ Cell State Conversion as a Bypass to KRASG12D Pharmacologic Inhibition in Metastatic Colorectal Cancer
Alessia Centonze, Adrià-Jaume Roura, Meritxell Novillo-Font, Cristina Giordano, Xavier Hernando‐Momblona, Montserrat Llanses Martinez, Pedro A Prats, Marta Sevillano, Débora Cabot, Mireia Novell, Gabriel Pabst, Florian Andersch, Adrià Cañellas‐Socias, Chong Zhang, Nickolaos Nikiforos Giakoumakis, Hugh Sparks, Christopher Dunsby, Julien Colombelli, Asunción Fernández‐Barral, Elena Sancho, Camille Stephan‐Otto Attolini, Alberto Múñoz, Antonio Barbáchano, Héctor G. Pálmer, Jordi Martínez‐Quintanilla, Johannes Zuber, Cristina Blaj, Elsa Quintana, Carme Cortina, Marc A. Martı́-Renom, Eduard Batlle
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.