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Loss of NOTCH2 creates a TRIM28-dependent vulnerability in small cell lung cancer
Deli Hong1, Ying Lyu2, Richa Nayak2
1Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
Abstract:
Small cell lung cancer (SCLC) is a highly aggressive malignancy that lacks effective targeted therapies, in part due to frequent loss-of-function mutations in tumor suppressors and the absence of recurrent oncogenic drivers. Approximately 15% of SCLCs harbor inactivating mutations in NOTCH1 or NOTCH2, and most neuroendocrine-high SCLCs exhibit low NOTCH activity. Using CRISPR-Cas9 screening in primary cell lines derived from NOTCH1/2-isogenic SCLC genetically engineered mouse models, we identified TRIM28 as a synthetic lethal dependency in NOTCH2-inactivated SCLCs. Loss of TRIM28 in this context robustly induced expression of endogenous retroviruses (ERVs), activated viral sensing pathways, and triggered a type I interferon response. Mechanistically, NOTCH2 inactivation increased reliance on TRIM28-mediated ERV silencing, creating a hyperdependence on TRIM28 via the STING-MAVS-TBK1 axis. Notably, TRIM28 was essential for tumor growth only in the setting of NOTCH2 loss. These findings identify TRIM28 as a potential therapeutic target in NOTCH2-deficient or low-NOTCH2-expressing SCLC.
Insights
Small cell lung cancer (SCLC) researchers found TRIM28 is essential for tumor growth when NOTCH2 is lost. Targeting TRIM28 may offer new therapies for NOTCH2-deficient SCLC.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Small cell lung cancer (SCLC) is an aggressive malignancy with limited targeted therapies.
- NOTCH1/NOTCH2 mutations occur in ~15% of SCLCs, often correlating with low NOTCH activity.
Purpose of the Study:
- To identify novel therapeutic targets in SCLC, particularly in tumors with NOTCH pathway alterations.
- To investigate the functional consequences of NOTCH2 inactivation in SCLC.
Main Methods:
- CRISPR-Cas9 screening in primary cell lines from genetically engineered mouse models of SCLC.
- Analysis of gene expression, viral sensing pathways, and interferon response.
- Investigation of the STING-MAVS-TBK1 signaling axis.
Main Results:
- TRIM28 was identified as a synthetic lethal dependency in NOTCH2-inactivated SCLCs.
- Loss of TRIM28 induced endogenous retroviruses (ERVs), activated viral sensing, and triggered a type I interferon response.
- TRIM28 loss created a hyperdependence via the STING-MAVS-TBK1 axis, essential for tumor growth only when NOTCH2 was lost.
Conclusions:
- TRIM28 is a critical vulnerability in NOTCH2-deficient SCLC.
- TRIM28 represents a potential therapeutic target for a subset of SCLC patients with NOTCH2 alterations.
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