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A plastic EMP1⁺ to LGR5⁺ cell state conversion as a therapeutic bypass to KRAS-G12D inhibition in metastatic colorectal cancer [scRNA-Seq]

ABSTRACT: Inhibitors of the oncogene KRAS holds promise for treating metastatic CRC (mCRC). Here we show that the activity of a small molecule RAS inhibitor, RM-044, which covalently binds to the G12D mutation in the active (ON) conformation of RAS, demonstrated strong curative effects in CRC models of early liver metastases, but its therapeutic activity was diminished in the advanced metastatic disease. RM-044-treated metastases underwent a fast transition from a poor-prognosis-associated Emp1⁺ transcriptional cell state to a WNT-driven Lgr5⁺ stem cell-like state that supported tumor growth in the absence of RAS G12D activity. This plastic conversion involved a switch in transcription factor usage, and did not require extensive chromatin remodeling. Enforced conversion of metastatic cells to the Lgr5⁺ state via RAS G12D inhibition, followed by genetic ablation of this population, produced strong therapeutic effects. Overall, these findings demonstrate a central role for oncogenic KRAS in governing cellular plasticity in mCRC.

ORGANISM(S): Mus musculus

PROVIDER: GSE294820 | GEO | 2025/09/29

REPOSITORIES: GEO

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A plastic EMP1⁺ to LGR5⁺ cell state conversion as a therapeutic bypass to KRAS-G12D inhibition in metastatic colorectal cancer [RNA-Seq human]

Project description:Inhibitors of the oncogene KRAS holds promise for treating metastatic CRC (mCRC). Here we show that the activity of a small molecule RAS inhibitor, RM-044, which covalently binds to the G12D mutation in the active (ON) conformation of RAS, demonstrated strong curative effects in CRC models of early liver metastases, but its therapeutic activity was diminished in the advanced metastatic disease. RM-044-treated metastases underwent a fast transition from a poor-prognosis-associated Emp1⁺ transcriptional cell state to a WNT-driven Lgr5⁺ stem cell-like state that supported tumor growth in the absence of RAS G12D activity. This plastic conversion involved a switch in transcription factor usage, and did not require extensive chromatin remodeling. Enforced conversion of metastatic cells to the Lgr5⁺ state via RAS G12D inhibition, followed by genetic ablation of this population, produced strong therapeutic effects. Overall, these findings demonstrate a central role for oncogenic KRAS in governing cellular plasticity in mCRC.

2025-09-29 | GSE294823 | GEO

A plastic EMP1⁺ to LGR5⁺ cell state conversion as a therapeutic bypass to KRAS-G12D inhibition in metastatic colorectal cancer [Hi-C]

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A plastic EMP1⁺ to LGR5⁺ cell state conversion as a therapeutic bypass to KRAS-G12D inhibition in metastatic colorectal cancer [ATAC-Seq]

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A plastic EMP1⁺ to LGR5⁺ cell state conversion as a therapeutic bypass to KRAS-G12D inhibition in metastatic colorectal cancer [SLAM-Seq]

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A plastic EMP1⁺ to LGR5⁺ cell state conversion as a therapeutic bypass to KRAS-G12D inhibition in metastatic colorectal cancer [RNA-Seq mouse]

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A plastic EMP1⁺ to LGR5⁺ cell state conversion as a therapeutic bypass to KRAS-G12D inhibition in metastatic colorectal cancer [RNA-Seq]

2025-09-29 | GSE303692 | GEO

A plastic EMP1⁺ to LGR5⁺ cell state conversion as a therapeutic bypass to KRAS-G12D inhibition in metastatic colorectal cancer

Project description:Most patients with metastatic colorectal cancer (mCRC) ultimately succumb to the disease due to a lack of effective therapeutic options. A new generation of inhibitors targeting the oncogene KRAS holds promise for treating mCRC and are currently under clinical investigation. In this study, we explore the activity of a small molecule KRAS inhibitor, RM-044, which covalently binds to the G12D mutation in the active (ON) conformation of KRAS. We found that despite robust inhibition of the KRAS signaling pathway, RM-044 exhibited limited therapeutic efficacy in patient-derived models of mCRC. Instead, liver metastases treated with RM-044 transitioned from a transcriptionally poor-prognosis-associated Emp1⁺ cell state to a WNT-driven Lgr5⁺ stem cell-like state that supported tumor growth even in the absence of KRAS-G12D activity. This plastic conversion occurred within hours of treatment, involved a switch in transcription factor usage, and did not require extensive chromatin remodeling. To explore vulnerabilities of RM-044–treated metastases, we engineered mCRC models to express the diphtheria toxin receptor under control of the Lgr5 locus. Enforced conversion of CRC cells to the Lgr5⁺ state via KRAS-G12D inhibition, followed by targeted ablation of this population using diphtheria toxin, produced strong therapeutic effects in the liver metastatic context.

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Dynamic conformational equilibria in the active states of KRas and NRas

Project description:The design of potent RAS inhibitors benefits from a molecular understanding of the dynamics in KRAS and NRAS and their oncogenic mutants. Here we characterize switch-1 dynamics in GTP-state KRAS and NRAS by 31P NMR, by 15N relaxation dispersion NMR, hydrogen-deuterium exchange mass spectrometry (HDX-MS), and molecular dynamics simulations. In GMPPNP-bound KRAS and NRAS, we see the co-existence of two conformational states, corresponding to an “inactive” state-1 and an “active” state-2, as previously reported. The KRAS oncogenic mutations G12D, G12C and G12V only slightly affect this equilibrium towards the “inactive” state-1, with rank order wt < G12C < G12D < G12V. In contrast, the NRAS Q61R oncogenic mutation shifts the equilibrium fully towards the “active” state-2. Our molecular dynamics simulations explain this by the observation of a transient hydrogen bond between the Arg61 side chain and the Thr35 backbone carbonyl oxygen. NMR relaxation dispersion experiments with GTP-bound KRAS Q61R confirm a drastic decrease in the population of state-1, but still detect a small residual population (1.8%) of this conformer. HDX-MS indicates that higher populations of state-1 correspond to increased hydrogen-deuterium exchange rates in some regions and increased flexibility, whereas low state-1 populations are associated with KRAS rigidification. We elucidated the mechanism of action of a potent KRAS G12D inhibitor, MRTX1133. Binding of this inhibitor to the switch-2 pocket causes a complete shift of KRAS G12D towards the “inactive” conformation and prevents binding of effector RAS-binding domain (RBD), by signaling through an allosteric network.

2025-05-07 | PXD054924 | Pride

MicroRNA expression profiling identified miR-31-5p/3p as associated with time to progression in wild-type KRAS metastatic colorectal cancer treated with cetuximab but not panitumumab

Project description:The aim of our study was to investigate whether miRNAs could serve as predictive biomarkers to anti-EGFR therapy (cetuximab, panitumumab) in patients with KRAS wild-type (wt-KRAS) metastatic colorectal cancer (mCRC). In our study, historical cohort of 96 patiens with wt-KRAS mCRC (2006-2009) was included and further divided into exploratory and validation cohorts. Large-scale miRNAs expression profiling was performed on the exploratory cohort of 41 wt-KRAS mCRC patients treated with cetuximab to identify miRNAs associated with time to progression (TTP). The validation was performed on two independent cohorts: 30 patients of wt-KRAS mCRC treated with cetuximab and 25 patients of wt-KRAS mCRC treated with panitumumab.

2016-05-05 | E-MTAB-3548 | biostudies-arrayexpress

Expression data comparing KRas(G12D/+);CreT, R26(H1047R/+);KRas(G12D/+);CreT, and MMTV-Neu mouse mammary tumors

Project description:Breast Cancer (BC) has been associated with alterations in signaling through a number of growth factor and hormone regulated pathways. Mouse models for metastatic BC have been developed using oncoproteins that activate PI3K, Stat3 and Ras signaling. To determine the role of each pathway, we analyzed mouse mammary tumor formation when they were activated singly or pairwise. We used microarrays to detect differentially expressed genes in the KRas(G12D/+);CreT and R26(H1047R/+);KRas(G12D/+);CreT tumors Total RNA was extracted from tumors developed by Qiagen RNAeasy kit and hybridized on Affymetrix microarrays.

2015-09-16 | E-GEOD-73073 | biostudies-arrayexpress

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