2025 Hot Topic in Basic & Translational Science: Small Cell Lung Cancer - Posters-PP01.08: FBXO11 mediates PARP inhibitor resistance in small-cell lung cancer

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This research study focuses on uncovering the mechanisms of resistance to PARP inhibitors (PARPi) in Small Cell Lung Cancer (SCLC), a particularly aggressive type of neuroendocrine tumor. The study identifies FBXO11, a component of the SCF E3 ubiquitin ligase, as a determinant of SCLC's response to PARPi treatment. Through a genome-wide CRISPR knockout screen, the researchers found that loss of FBXO11 leads to resistance against PARPi, including talazoparib.<br /><br />Further investigation reveals that FBXO11 interacts with the XAB2 complex, a pre-mRNA splicing complex, which includes proteins like XAB2, AQR, and ISY1. These interactions suggest that FBXO11 plays a role in regulating alternative splicing, particularly of genes involved in DNA damage response and apoptosis, offering a potential mechanistic link to PARPi resistance.<br /><br />The researchers applied several methods, including RNA sequencing, proteomics (BioID-MS), and luciferase splicing reporter assays, to explore these interactions and mechanisms. They found that loss of FBXO11 alters the function and interactions (like decreased PLA intensities between XAB2 & AQR, and AQR & ISY1) involved in the splicing complex, promoting PARPi resistance.<br /><br />Moreover, FBXO11 is shown to promote K63-linked ubiquitination of XAB2, a modification that might influence splicing or cellular stress responses. Following FBXO11 knockout, there was a significant reduction in γH2AX foci formation, indicating impaired DNA damage response in the presence of PARPi.<br /><br />Overall, the study suggests that FBXO11 and the associated XAB2 complex could serve as predictive biomarkers for PARPi sensitivity in SCLC. Future work includes examining alternatively spliced genes to further elucidate the pathways critical for the cellular response to such treatments. This knowledge could lead to more personalized treatment strategies for SCLC patients.

Asset Subtitle

Jiaqi Xiong

Keywords

PARP inhibitors

Small Cell Lung Cancer

FBXO11

SCF E3 ubiquitin ligase

CRISPR knockout screen

XAB2 complex

alternative splicing

DNA damage response

predictive biomarkers

personalized treatment