ArticleCancer discovery2026
A Plastic EMP1+ to LGR5+ Cell State Conversion as a Bypass to KRASG12D Pharmacologic Inhibition in Metastatic Colorectal Cancer.
Article in Cancer discovery, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- Advances in Bispecific Antibodies and Antibody-Drug Conjugates for Colorectal Cancer Treatment.Antibodies (Basel, Switzerland) · 2026Review
- Article
- Progressive intestinal tumor cell plasticity, Myc activation, and loss of Lgr5Science advances · 2026Article
- RAS Inhibitors: Changing the Paradigm from the Undruggable.Pharmaceutics · 2026Review
- LGR5: from stem cell marker to therapeutic target.Trends in cancer · 2026Review
- Ras-MAPK inhibition induces AXIN1 loss in colorectal cancer by mTOR associated suppression of protein synthesis.Cell communication and signaling : CCS · 2026Article
- Review
- Diversion ostomy improves treatment tolerance, conversion surgery, and survival compared with self-expanding metal stenting in initially unresectable obstructive colorectal cancer.Frontiers in oncology · 2026Article
- Understanding Liver and Digestive Diseases: A Paved Road to Improve Diagnosis, Management, and Treatment.Exploration of digestive diseases · 2026Article
- Review
Corrections and comments
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Authors and funding
31 authors.
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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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.