ArticlebioRxiv : the preprint server for biology2026
Radiosensitization of Glioblastoma by the K-ras Inhibitor RMC-6236.
Article in bioRxiv : the preprint server for biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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6 authors.
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Abstract
Purpose: Glioblastoma (GBM) is characterized by poor clinical outcomes and marked resistance to radiotherapy. Because effective radiosensitizing strategies for GBM remain limited, we investigated whether inhibition of KRAS/RAS signaling could enhance radiation response in GBM. In particular, we evaluated the radiosensitizing potential of RMC-6236, an RAS(ON) multiselective inhibitor that suppresses active RAS signaling across multiple RAS-dependent states. Experimental Design: Human GBM cell lines (U251, LN-18, ACPK1, and OSU61) were treated with radiation, with or without genetic or pharmacological KRAS inhibition. KRAS signaling was suppressed by siRNA-mediated knockdown or RMC-6236 treatment. Radiation-induced KRAS activation and downstream MAPK signaling were assessed by Raf-RBD pull-down assays and immunoblotting. Radiosensitivity was evaluated using clonogenic survival assay. DNA damage persistence, cell cycle distribution, and mitotic catastrophe were analyzed by γH2AX immunofluorescence, flow cytometry, and nuclear morphology assessment, respectively. In vivo therapeutic efficacy was examined in an orthotopic U251 xenograft model. Results: Radiation-induced transient activation and increased KRAS protein expression of KRAS, accompanied by activation of ERK, JNK, and p38 signaling in GBM cells. siKRAS suppressed radiation-induced KRAS and MAPK activation, and significantly enhanced radiosensitivity in all four GBM cell lines. Similarly, RMC-6236 inhibited radiation-induced KRAS activation and attenuated downstream MAPK signaling without reducing the total KRAS protein expression. RMC-6236 significantly increased the radiosensitivity across all GBM cell lines, with dose enhancement factors ranging from 1.33 1.46. Mechanistically, combined treatment with RMC-6236 and radiation increased persistent γH2AX foci and enhanced mitotic catastrophe without producing consistent redistribution of cells into radiosensitive cell cycle phases. In an orthotopic GBM model, the combination of RMC-6236 and radiation significantly prolonged survival compared to that of the control and radiation alone. Conclusions: These findings indicate that radiation-induced KRAS signaling is a functionally important mediator of radioresistance in GBM and demonstrate that inhibition of KRAS/RAS signaling enhances the radiation response
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