Concurrent genetic and non-genetic resistance mechanisms to KRAS inhibition in CRC.

ABSTRACT: KRAS is mutationally activated in 45-50% of colorectal cancer (CRC) cases, and while KRAS-targeted therapies have shown some clinical promise, upfront and acquired resistance limit their efficacy. To explore the acute response and mechanisms underlying KRAS inhibitor resistance, we used targeted exome sequencing and single-cell spatial transcriptomics to analyze patient-matched pre-treatment, on-treatment, and progression biopsies from patients treated with combined KRAS^G12C and EGFR inhibition. Acquired genetic events were identified in most patients at progression but were often subclonal and coexisted with transcriptional adaptive states. Mesenchymal, YAP, and fetal-like transcriptional signatures predominated in resistant tumors, while tumor cell-intrinsic inflammatory progr

SUBMITTER: Alonso S 

PROVIDER: S-EPMC12340827 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature