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| Home > Publications database > Reporter-based screening identifies RAS-RAF mutations as drivers of resistance to active-state RAS inhibitors in colorectal cancer. |
| Home > Publications database > Reporter-based screening identifies RAS-RAF mutations as drivers of resistance to active-state RAS inhibitors in colorectal cancer. |
| Journal Article | DKFZ-2025-01522 |
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2025
Assoc.
Washington, DC [u.a.]
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Please use a persistent id in citations: doi:10.1126/scisignal.adr3738
Abstract: Therapy-induced acquired resistance limits the clinical effectiveness of mutation-specific KRAS inhibitors in colorectal cancer (CRC). Here, we investigated whether broad-spectrum, active-state RAS inhibitors meet similar limitations. We found that KRAS-mutant CRC cell lines were sensitive to the RAS(ON) multiselective RAS inhibitor RMC-7977, given that treatment resulted in RAS-RAF-MEK-ERK pathway inhibition; halted proliferation; and, in some cases, induced apoptosis. RMC-7977 initially reduced the activity of a compartment-specific, dual-color reporter of ERK activity, with reporter reactivation emerging after long-term dose escalation. These drug-resistant cell populations exhibited distinct patterns of phospho-protein abundance, transcriptional activities, and genomic mutations, including a Y71H mutation in KRAS and an S257L mutation in RAF1. Transgenic expression of KRASG13D, Y71H or RAF1S257L in drug-sensitive CRC cells induced resistance to RMC-7977. CRC cells that were resistant to RMC-7977 and harboring RAF1S257L exhibited synergistic sensitivity to concurrent inhibition of RAS and RAF. Our findings demonstrate the power of reporter-assisted screening together with single-cell analyses for dissecting the complex landscape of therapy resistance. The strategy offers opportunities to develop clinically relevant combinatorial treatments to counteract the emergence of resistant cancer cells.
Keyword(s): Humans (MeSH) ; Colorectal Neoplasms: genetics (MeSH) ; Colorectal Neoplasms: drug therapy (MeSH) ; Colorectal Neoplasms: pathology (MeSH) ; Colorectal Neoplasms: metabolism (MeSH) ; Drug Resistance, Neoplasm: genetics (MeSH) ; Drug Resistance, Neoplasm: drug effects (MeSH) ; Proto-Oncogene Proteins c-raf: genetics (MeSH) ; Proto-Oncogene Proteins c-raf: metabolism (MeSH) ; Proto-Oncogene Proteins p21(ras): genetics (MeSH) ; Proto-Oncogene Proteins p21(ras): antagonists & inhibitors (MeSH) ; Proto-Oncogene Proteins p21(ras): metabolism (MeSH) ; Cell Line, Tumor (MeSH) ; Mutation (MeSH) ; Genes, Reporter (MeSH) ; MAP Kinase Signaling System: drug effects (MeSH) ; MAP Kinase Signaling System: genetics (MeSH) ; Apoptosis: drug effects (MeSH) ; Proto-Oncogene Proteins c-raf ; Proto-Oncogene Proteins p21(ras) ; KRAS protein, human ; Raf1 protein, human
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