2. Academic Validation
  3. Loss of NOTCH2 creates a TRIM28-dependent vulnerability in small cell lung cancer

Loss of NOTCH2 creates a TRIM28-dependent vulnerability in small cell lung cancer

  • Dev Cell. 2025 Aug 25:S1534-5807(25)00499-X. doi: 10.1016/j.devcel.2025.07.023.
Deli Hong 1,  Ying Lyu 2,  Richa Nayak 2,  Justin S Becker 3,  Matthew A Booker 4,  Keita Masuzawa 1,  Zoe Devos 1,  Tianchu Wang 1,  Shin Saito 1,  Qi Liu 5,  Yixiang Li 1,  Zhaorong Li 4,  Eric H Knelson 1,  Tran Thai 1,  Leslie Duplaquet 1,  Yasmin N Laimon 6,  Gabriel Roberti De Oliveira 6,  Sabina Signoretti 7,  John G Doench 8,  David A Barbie 1,  Michael Y Tolystorukov 4,  Jun Qi 5,  Bradley E Bernstein 5,  Yejing Ge 2,  Matthew G Oser 9
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
  • 2 Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 3 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.
  • 4 Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 5 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 6 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 7 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 8 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 9 Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA. Electronic address: matthew_oser@dfci.harvard.edu.
PMID: 40865518 DOI: 10.1016/j.devcel.2025.07.023
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.

Keywords

CRISPR-Cas9 screening; NOTCH2; TRIM28; endogenous retroviruses; small cell lung cancer; synthetic lethality; viral sensing.

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