2023 Targeted Therapies of Lung Cancer Meeting (Poster)-P1.22. Mutations in Spliceosome Genes, SRSF2 and FUBP1, in NSCLC Are Associated with Multiple Actionable Driver Mutations, Notably KRAS G12C/V and EGFR L858R as Well as STK11/KEAP1 Mutations without Actionable Driver Mutations. Results Collected from a Survey of cBioPortal GENIE Database

P1.22. Mutations in Spliceosome Genes, SRSF2 and FUBP1, in NSCLC Are Associated with Multiple Actionable Driver Mutations, Notably KRAS G12C/V and EGFR L858R as Well as STK11/KEAP1 Mutations without Actionable Driver Mutations. Results Collected from a Survey of cBioPortal GENIE Database

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Researchers from the University of California Department of Medicine and Chao Family Comprehensive Cancer Center have identified aberrant slicing mechanisms in various cancers, which could be targeted for the development of new therapies. In particular, mutations in five RNA splicing genes - RBM10, U2AF1, SF3B1, SRSF2, and FUBP1 - are commonly found in non-small cell lung cancer (NSCLC). SRSF2 is an auxiliary splicing factor that enhances splicing by binding to specific motifs, while FUBP1 mediates exon skipping by binding to AT-rich exons. Mutations in these genes are associated with down-regulation of alternative splicing and MYC-target genes. The researchers found that mutations in SRSF2 and FUBP1 in NSCLC are strongly associated with actionable driver mutations, particularly KRAS G12C/V and EGFR L858R mutations. In their analysis of the cBioPortal GENIE database, they found that FUBP1 mutations co-occur with established actionable driver mutations in 46% of cases, with KRAS G12C being the most common (33%), followed by EGFR L858R (20%). For SRSF2 mutations, 35% co-occurred with actionable driver mutations, with EGFR E746 (14%), KRAS G12C (26%), and KRAS G12V (14%) being the most common. The researchers evaluated 105 cases of SRSF2 mutations and 87 cases of FUBP1 mutations in a total of 19,046 NSCLC samples. They found that the majority of patients were White (74%), followed by Asian (8%) and Black (4%). These findings suggest that targeting RNA splicing, alone or in combination with specific on-target inhibition, could improve the therapeutic efficacy of current targeted therapy and immunotherapy treatment regimens for NSCLC.

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Alexandria Lee, University of California Irvine School of Medicine Department of Internal Medicine, United States

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Speaker Alexandria Lee, University of California Irvine School of Medicine Department of Internal Medicine, United States

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Keywords

aberrant slicing mechanisms

RNA splicing genes

non-small cell lung cancer

SRSF2 mutations

FUBP1 mutations

alternative splicing

MYC-target genes

actionable driver mutations

KRAS G12C/V

EGFR L858R