U2AF1 mutations rescue deleterious exon skipping induced by KRAS mutations

Area of Science:

• Molecular Biology
• Cancer Genomics
• Splicing Factor Function

Background:

• Mechanisms linking splicing factor mutations (e.g., U2AF1^S34F) to lung adenocarcinoma pathogenesis remain unclear.
• Splicing alterations are increasingly recognized as drivers of cancer development.

Purpose of the Study:

• To investigate the functional impact of U2AF1 mutations on alternative splicing in lung adenocarcinoma.
• To identify key oncogenic targets modulated by splicing factor mutations.

Main Methods:

• Utilized prime editing to engineer endogenous U2AF1 mutations in lung adenocarcinoma cells.
• Performed alternative splicing analyses to assess transcriptomic changes.
• Analyzed cancer genome and clinical patient data for mutation co-occurrence and survival correlations.

Main Results:

• Identified KRAS as a direct target of U2AF1^S34F, with U2AF1^S34F rescuing KRAS exon 2 skipping caused by KRAS^G12S.
• Found enrichment of U2AF1^S34F mutations in KRAS^G12S-mutant lung adenocarcinomas.
• Demonstrated that U2AF1^I24T can rescue KRAS exon 3 skipping induced by KRAS^Q61R, with both U2AF1 mutations occurring secondary to KRAS mutations and associated with poorer survival.

Conclusions:

• Splicing factor mutations can act as suppressors of splicing defects introduced by oncogenic mutations, particularly in KRAS.
• These findings highlight a cascading selection mechanism in cancer evolution where secondary mutations rescue the functional impact of primary oncogenic events.
• U2AF1 mutations in lung adenocarcinoma may represent a compensatory response to KRAS oncogene activation.