Sun Nai-Yun, Kumar Suresh, Kim Yoo Sun, Varghese Diana, Mendoza Arnulfo, Nguyen Rosa, Okada Reona, Reilly Karlyne, Widemann Brigitte, Pommier Yves, Elloumi Fathi, Dhall Anjali, Taniyama Daiki, Patel Mayank, Aber Etan, Contreras Cristina F, Kaplan Rosandra N, Kiseljak-Vassiliades Katja, Wierman Margaret E, Martinez Dan, Pogoriler Jennifer, Hamilton Amber K, Diskin Sharon J, Maris John M, Robey Robert W, Gottesman Michael M, Del Rivero Jaydira, Roper Nitin
Developmental Therapeutics Branch, Center for Cancer Research, NCI, Bethesda, MD, USA.
Pediatric Oncology Branch, Center for Cancer Research, NCI, Bethesda, MD, USA.
Nat Commun. 2025 Jul 1;16(1):5511. doi: 10.1038/s41467-025-60649-w.
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).
虽然针对细胞表面蛋白的免疫治疗是一种越来越有效的癌症治疗方法，但识别新的表面蛋白，尤其是那些具有生物学重要性的蛋白，至关重要。在此，我们发现δ样非经典Notch配体1（DLK1）是一种细胞表面蛋白，在正常组织中表达有限，而在多种难治性成人转移性癌症中高表达，包括小细胞肺癌（SCLC）和肾上腺皮质癌（ACC），后者是一种有效治疗方法很少的罕见癌症。在ACC中，靶向DLK1的抗体药物偶联物（ADC）ADCT-701显示出体外和体内活性，但由于药物外排蛋白ABCB1（MDR1，P-糖蛋白）的高表达和活性，总体活性有限。相比之下，ADCT-701在ABCB1低表达或无表达的DLK1阳性ACC和SCLC体内模型中诱导完全缓解。ACC中DLK1的基因缺失显著下调ABCB1，并通过NOTCH1介导的转分化增加ADC有效载荷和化疗敏感性。这项工作将DLK1确定为一种免疫治疗靶点，其可调节ACC中的肿瘤细胞可塑性和化疗耐药性，并支持在ACC和神经内分泌肿瘤中开展一项针对DLK1使用ADC的I期临床试验（NCT06041516）。
