Identification of the Notch ligand DLK1 as an immunotherapeutic target and regulator of tumor cell plasticity and chemoresistance in adrenocortical carcinoma

  • Nat Commun. 2025 Jul 1;16(1):5511. doi: 10.1038/s41467-025-60649-w.
Nai-Yun Sun  1 ,  Suresh Kumar  1 ,  Yoo Sun Kim  1 ,  Diana Varghese  1 ,  Arnulfo Mendoza  2 ,  Rosa Nguyen  2 ,  Reona Okada  2 ,  Karlyne Reilly  2 ,  Brigitte Widemann  2 ,  Yves Pommier  1 ,  Fathi Elloumi  1 ,  Anjali Dhall  1 ,  Daiki Taniyama  1 ,  Mayank Patel  3 ,  Etan Aber  2 ,  Cristina F Contreras  2 ,  Rosandra N Kaplan  2 ,  Katja Kiseljak-Vassiliades  4  5 ,  Margaret E Wierman  4 ,  Dan Martinez  6 ,  Jennifer Pogoriler  6 ,  Amber K Hamilton  7 ,  Sharon J Diskin  7 ,  John M Maris  7 ,  Robert W Robey  8 ,  Michael M Gottesman  8 ,  Jaydira Del Rivero  1 ,  Nitin Roper  9
Affiliations
  • 1. Developmental Therapeutics Branch, Center for Cancer Research, NCI, Bethesda, MD, USA.
  • 2. Pediatric Oncology Branch, Center for Cancer Research, NCI, Bethesda, MD, USA.
  • 3. Laboratory of Pathology, Center for Cancer Research, NCI, Bethesda, MD, USA.
  • 4. Department of Medicine-Endocrinology/Metabolism/Diabetes, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
  • 5. Research Service Rocky Mountain, Regional Veterans Affairs Medical Center, Aurora, CO, USA.
  • 6. Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 7. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, and Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 8. Laboratory of Cell Biology, Center for Cancer Research, NCI, Bethesda, MD, USA.
  • 9. Developmental Therapeutics Branch, Center for Cancer Research, NCI, Bethesda, MD, USA. [email protected].
PMID: 40595495 DOI: 10.1038/s41467-025-60649-w
Abstract

While immunotherapeutic targeting of cell surface proteins is an increasingly effective Cancer therapy, identification of new surface proteins, particularly those with biological importance, is critical. Here, we uncover delta-like non-canonical Notch ligand 1 (DLK1) as a cell surface protein with limited normal tissue expression and high expression in multiple refractory adult metastatic cancers including small cell lung Cancer (SCLC) and adrenocortical carcinoma (ACC), a rare Cancer with few effective therapies. In ACC, ADCT-701, a DLK1 targeting antibody-drug conjugate (ADC), shows in vitro and in vivo activity but is overall limited due to high expression and activity of the drug efflux protein ABCB1 (MDR1, P-glycoprotein). In contrast, ADCT-701 induces complete responses in DLK1+ ACC and SCLC in vivo models with low or no ABCB1 expression. Genetic deletion of DLK1 in ACC dramatically downregulates ABCB1 and increases ADC payload and chemotherapy sensitivity through NOTCH1-mediated transdifferentiation. This work identifies DLK1 as an immunotherapeutic target that regulates tumor cell plasticity and chemoresistance in ACC and supports an active phase I clinical trial targeting DLK1 with an ADC in ACC and neuroendocrine neoplasms (NCT06041516).

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