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A Plastic EMP1+ to LGR5+ Cell State Conversion as a Bypass to KRASG12D Pharmacologic Inhibition in Metastatic
Alessia Centonze1,2, Adrià-Jaume Roura1,2, Meritxell Novillo-Font3,4
1Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
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.
Insights
KRAS inhibitors show promise for metastatic colorectal cancer (mCRC). However, advanced mCRC cells adapt to RMC-9945 by becoming Lgr5+ stem cells, requiring new therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Oncogenic KRAS mutations are key drivers in metastatic colorectal cancer (mCRC).
- Targeting the active RAS-G12D conformation with small molecule inhibitors like RMC-9945 offers a therapeutic strategy.
Purpose of the Study:
- To investigate the efficacy of RMC-9945, a covalent inhibitor of active RAS-G12D, in preclinical mCRC models.
- To understand the adaptive mechanisms of mCRC metastases upon treatment with RAS(ON) inhibitors.
Main Methods:
- Utilized preclinical CRC models with early and advanced liver metastases.
- Administered RMC-9945 and analyzed transcriptional state changes (Emp1+, Lgr5+).
- Investigated transcription factor dynamics and chromatin remodeling.
- Employed genetic ablation strategies in combination with RMC-9945.
Main Results:
- RMC-9945 demonstrated durable disease control in early liver metastases but reduced efficacy in advanced disease.
- Metastases transitioned from an Emp1+ state to a WNT-driven, Lgr5+ stem cell-like state resistant to RAS-G12D inhibition.
- This adaptive cell state change occurred rapidly, involving transcription factor shifts with minimal chromatin remodeling.
- Combined RAS-G12D inhibition and Lgr5+ cell ablation reduced metastatic burden and improved survival in a mouse mCRC model.
Conclusions:
- Oncogenic KRAS plays a critical role in regulating cellular plasticity within mCRC.
- Adaptive resistance to RAS inhibitors involves a rapid transition to a stem cell-like state.
- Targeting KRAS-driven cellular plasticity is a potential strategy for overcoming therapeutic resistance in mCRC.
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