2023 North America Conference on Lung Cancer (NACLC) - Posters and Abstracts-PP01.121 (Poster) Analysis of Degron Disruption in Small Cell Lung Cancer

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A recent study conducted by the Mayo Foundation for Medical Education and Research focused on analyzing degron disruptions in small cell lung cancer (SCLC). The Ubiquitin-Proteasome System (UPS), which is responsible for regulating the degradation of cellular proteins, is often disrupted in cancer, including SCLC. One way in which the UPS can become dysregulated is through the disruption of degron sequences. <br /><br />Degrons are short sequences within proteins that are recognized and bound by E3 ubiquitin ligases, which are critical components of the UPS. The binding of the E3 ligase leads to the transfer of ubiquitins to the target protein, marking it for degradation by the proteasome. Degron binding sites can be found within the internal sequence or at the terminal ends of the protein. <br /><br />The study developed a bioinformatics workflow to identify degron disruptions in 103 cases of SCLC. Various degron disruptions driving cancer have been identified in other types of cancer, such as the Ex14 skipping event in the MET gene in Non-Small Cell Lung Cancer (NSCLC). This event results in the loss of the E3 ligase binding site, leading to abnormal stabilization and accumulation of the Hepatocyte Growth Factor Receptor.<br /><br />The study also found that missense mutations in the degron sequence of the β-catenin gene are considered one of the most abundant mutations driving carcinogenesis in various cancers. The loss of proper degradation of β-catenin results in the continued transcription of WNT signaling genes, leading to cell proliferation.<br /><br />In addition, the study identified structural rearrangements in the TP73 gene, resulting in Ex2 and Ex3 skipping in some samples. This leads to the loss of a well-characterized degron motif shared by TP73, TP53, and TP63. However, the specific consequences of this degron loss in TP73 require further investigation.<br /><br />Overall, the study highlights the importance of degron disruptions in cancer, including small cell lung cancer. Understanding these disruptions can provide insights into potential therapeutic targets and treatment strategies.

Asset Subtitle

Kimberly Lauer

Keywords

degron disruptions

small cell lung cancer

Ubiquitin-Proteasome System

E3 ubiquitin ligases

proteasome degradation

Ex14 skipping event

MET gene

Hepatocyte Growth Factor Receptor

missense mutations

WNT signaling genes