BibTex format
@article{Centonze:2025:10.1158/2159-8290.CD-25-0679,
author = {Centonze, A and Roura, A-J and Novillo-Font, M and Giordano, C and Hernando-Momblona, X and Llanses, M and Prats, P and Sevillano, M and Cabot, D and Novell, M and Pabst, G and Andersch, F and Cañellas-Socias, A and Zhang, C and Giakoumakis, N-N and Sparks, H and Dunsby, C and Colombelli, J and Fernández-Barral, A and Sancho, E and Stephan-Otto, Attolini C and Muñoz, A and Barbachano, A and Palmer, HG and Martínez-Quintanilla, J and Zuber, J and Blaj, C and Quintana, E and Cortina, C and Marti-Renom, MA and Batlle, E},
doi = {10.1158/2159-8290.CD-25-0679},
journal = {Cancer Discov},
title = {A plastic EMP1 to LGR5 cell state conversion as a bypass to KRAS-G12D pharmacological inhibition in metastatic colorectal cancer.},
url = {http://dx.doi.org/10.1158/2159-8290.CD-25-0679},
year = {2025}
}
RIS format (EndNote, RefMan)
TY - JOUR
AB - Inhibitors of the oncogene KRAS hold promise for treating metastatic CRC (mCRC). Here 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 CRC 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.
AU - Centonze,A
AU - Roura,A-J
AU - Novillo-Font,M
AU - Giordano,C
AU - Hernando-Momblona,X
AU - Llanses,M
AU - Prats,P
AU - Sevillano,M
AU - Cabot,D
AU - Novell,M
AU - Pabst,G
AU - Andersch,F
AU - Cañellas-Socias,A
AU - Zhang,C
AU - Giakoumakis,N-N
AU - Sparks,H
AU - Dunsby,C
AU - Colombelli,J
AU - Fernández-Barral,A
AU - Sancho,E
AU - Stephan-Otto,Attolini C
AU - Muñoz,A
AU - Barbachano,A
AU - Palmer,HG
AU - Martínez-Quintanilla,J
AU - Zuber,J
AU - Blaj,C
AU - Quintana,E
AU - Cortina,C
AU - Marti-Renom,MA
AU - Batlle,E
DO - 10.1158/2159-8290.CD-25-0679
PY - 2025///
TI - A plastic EMP1 to LGR5 cell state conversion as a bypass to KRAS-G12D pharmacological inhibition in metastatic colorectal cancer.
T2 - Cancer Discov
UR - http://dx.doi.org/10.1158/2159-8290.CD-25-0679
UR - https://www.ncbi.nlm.nih.gov/pubmed/41128661
ER -