Identification of the Notch ligand DLK1 as an immunotherapeutic target and regulator of tumor cell plasticity and chemoresistance in adrenocortical carcinoma
- Nai-Yun Sun
- Suresh Kumar
- Yoo Sun Kim
- Diana Varghese
- Arnulfo Mendoza
- Rosa Nguyen
- Reona Okada
- Karlyne Reilly
- Brigitte Widemann
- Yves Pommier
- Fathi Elloumi
- Anjali Dhall
- Daiki Taniyama
- Mayank Patel
- Etan Aber
- Cristina F. Contreras
- Rosandra N. Kaplan
- Katja Kiseljak-Vassiliades
- Margaret E. Wierman
- Dan Martinez
- Jennifer Pogoriler
- Amber K. Hamilton
- Sharon J. Diskin
- John M. Maris
- Robert W. Robey
- Michael M. Gottesman
- Jaydira Del Rivero
- Nitin Roper
2025-07-01
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).