Developmental cellAug 27, 2025

Loss of NOTCH2 creates a TRIM28-related weakness in small cell lung cancer

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 20, 2026

Abstract

Approximately 15% of small cell lung cancers harbor inactivating mutations in NOTCH1 or NOTCH2.

Inhibition of TRIM28 was found to robustly induce the expression of endogenous retroviruses in NOTCH2-inactivated small cell lung cancer.
Loss of TRIM28 activated viral sensing pathways and triggered a type I interferon response.
Inactivation of NOTCH2 increased the reliance on TRIM28 for silencing of endogenous retroviruses.
TRIM28 was necessary for tumor growth specifically in the context of NOTCH2 loss.
These observations suggest that targeting TRIM28 may be a viable therapeutic strategy for NOTCH2-deficient small cell lung cancer.

Simplified

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.

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Funding

Competing interests

Declaration of interests M.G.O. reports grants from Novartis, Auron Therapeutics, Circle Pharma, Eli Lilly, Takeda, and BMS, none of which are related to this work. J.Q. is a scientific co-founder and consultant for Epiphanes and scientific consultant for Talus Bio. D.A.B. is a consultant for N of One/Qiagen and Exo Therapeutics, is a founder and shareholder in Xsphera Biosciences, has received honoraria from Merck, H3 Biomedicine/Esai, EMD Serono, Gilead Sciences, AbbVie, and Madalon Consulting and research grants from BMS, Takeda, Novartis, Gilead, and Lilly and Daiichi Sankyo. E.H.K. is an employee and shareholder of Merck & Co.

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Loss of NOTCH2 creates a TRIM28-related weakness in small cell lung cancer

Abstract

Full Text

Funding

Competing interests

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