2025 Hot Topic in Basic & Translational Science: Small Cell Lung Cancer - Posters-PP01.07: Identification of Synthetic Lethal Vulnerabilities Between TRIM28 and NOTCH2 in Small Cell Lung Cancer Through CRISPR/Cas9 Screening

PP01.07: Identification of Synthetic Lethal Vulnerabilities Between TRIM28 and NOTCH2 in Small Cell Lung Cancer Through CRISPR/Cas9 Screening

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This research investigates synthetic lethal vulnerabilities in Small Cell Lung Cancer (SCLC) with a focus on mutations in the NOTCH receptors. Such mutations are prevalent in various cancers, especially SCLC, which is notoriously difficult to treat. The study utilized CRISPR/Cas9 technology to create genetically engineered mouse models to generate NOTCH1 and NOTCH2 mutant, as well as NOTCH wild-type SCLC tumors. From these, primary cell lines were derived, and CRISPR/Cas9 loss-of-function screens identified synthetic lethal dependencies associated with NOTCH mutations.<br /><br />The results revealed that NOTCH2-inactivated SCLC cells showed heightened dependency on the transcriptional regulator TRIM28, also known as KAP1/TIF1B. When TRIM28 was inactivated in NOTCH2-inactivated SCLC cells, there was a significant induction of endogenous retroviruses, viral sensing proteins, and Type I interferon response genes. It indicated a hyperactivation of viral sensing pathways, which is cytotoxic to the cancer cells. This hyper-dependence was shown to be modulated via the STING1/MAVS-TBK1 pathway, emphasizing the role of these pathways in driving synthetic lethality when combined with TRIM28 inactivation.<br /><br />In both immunocompetent and immunocompromised NOTCH2-inactivated SCLC xenografts, TRIM28 inactivation effectively inhibited tumor growth, underlining its potential as a therapeutic target. The study concludes that targeting TRIM28 may be a viable therapeutic strategy for treating SCLC with low functional NOTCH2 levels, urging further exploration into TRIM28 inhibition in such contexts. This research advances the understanding of genetic vulnerabilities in SCLC, potentially opening new avenues for targeted treatment strategies.

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Deli Hong

Keywords

Small Cell Lung Cancer

SCLC

NOTCH mutations

CRISPR/Cas9

synthetic lethality

TRIM28

endogenous retroviruses

STING1/MAVS-TBK1 pathway

tumor growth inhibition

therapeutic target