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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\u2013treated metastases underwent a transition from a poor prognosis\u2013associated Emp1+ transcriptional state to a WNT-driven Lgr5+ stem cell\u2013like 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>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\u2013like state. Our findings highlight the context-dependent effects of oncogenic KRAS mutations and underscore cell plasticity as a therapeutic opportunity.<\/jats:p>\n                    <jats:p>See related commentary by Eng and Yilmaz et al., p. 201<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-25-0679","type":"journal-article","created":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T14:01:21Z","timestamp":1761228081000},"page":"320-344","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["A Plastic EMP1+ to LGR5+ Cell State Conversion as a Bypass to KRASG12D Pharmacologic Inhibition in Metastatic Colorectal Cancer"],"prefix":"10.1158","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4269-1933","authenticated-orcid":false,"given":"Alessia","family":"Centonze","sequence":"first","affiliation":[{"name":"1Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of 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