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Effects of active-state RAS inhibition on the colorectal cancer cell transcriptome

ABSTRACT: Here, we identified and categorized mechanisms of resistance to broad-spectrum active-state RAS inhibition in colorectal cancer cell lines. Emerging resistant cell populations after long-term dose escalation revealed distinct patterns of genomic mutations and phospho-protein states. To assess transcriptomic footprints associated with RASi resistance, we employed single cell RNA sequencing. We compared parental DLD1 and SW480 cells, and RASi-resistant sublines termed DLD1-FIREX-high, DLD1-FIREX-low, DLD1-cFIREX-high and SW480-resistant. Cells were cultured in the absence or presence of ERK or RAS inhibitors as indicated. This experimental design enables the identification of transcriptomic shifts induced by RAS and ERK inhibition, thereby facilitating assessment of their reactivation upon emergence of secondary resistance. Finally, we used SW480-et cells expressing a murine Eco receptor. These cells were transfected with lentiviral oncogene vectors and subsequently cultured for 72h in the absence or presence of RAS inhibitor. We find that the subpopulations show different levels of pathway activities, including MAPK. Our findings endorse single-cell analyses as a powerful approach for dissecting the complex landscape of therapy resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE287188 | GEO | 2025/12/12

REPOSITORIES: GEO

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Effects of active-state RAS inhibition on the colorectal cancer cell transcriptome

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