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
  • 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: [email protected].
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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