Alam Sk Kayum, Pandit Anuradha, Wang Li, Mortazavi Farsani Seyedeh Sahar, Thiele Britteny A, Manoj Parvathy, Aubry Marie Christine, Verma Vivek, Rudin Charles M, Lo Ying-Chun, Hoeppner Luke H
The Hormel Institute, University of Minnesota, Austin, MN, USA.
Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Cell Death Dis. 2025 May 9;16(1):370. doi: 10.1038/s41419-025-07693-y.
Small cell lung cancer (SCLC) is difficult to treat due to its aggressiveness, early metastasis, and rapid development of resistance to chemotherapeutic agents. Here, we show that treatment with a dopamine D receptor (DR) agonist reduces tumour angiogenesis in multiple in vivo xenograft models of human SCLC, thereby reducing SCLC progression. An FDA-approved DR agonist, cabergoline, also sensitized chemotherapy-resistant SCLC tumours to cisplatin and etoposide in patient-derived xenograft models of acquired chemoresistance in mice. Ex vivo, DR agonist treatment decreased tumour angiogenesis through increased apoptosis of tumour-associated endothelial cells, creating a less favourable tumour microenvironment that limited cancer cell proliferation. In paired SCLC patient-derived specimens, DR was expressed by tumour-associated endothelial cells obtained before treatment, but DR was downregulated in SCLC tumours that had acquired chemoresistance. DR agonist treatment of chemotherapy-resistant specimens restored expression of DR. Activation of dopamine signalling is thus a new strategy for inhibiting angiogenesis in SCLC and potentially for combatting chemotherapy-refractory SCLC progression.
小细胞肺癌（SCLC）因其侵袭性、早期转移以及对化疗药物迅速产生耐药性而难以治疗。在此，我们表明，在多种人SCLC体内异种移植模型中，用多巴胺D受体（DR）激动剂进行治疗可减少肿瘤血管生成，从而减少SCLC进展。一种经美国食品药品监督管理局（FDA）批准的DR激动剂卡麦角林，在小鼠获得性化疗耐药的患者来源异种移植模型中，也使化疗耐药的SCLC肿瘤对顺铂和依托泊苷敏感。在体外，DR激动剂治疗通过增加肿瘤相关内皮细胞的凋亡来减少肿瘤血管生成，从而营造出一个不利于癌细胞增殖的肿瘤微环境。在配对的SCLC患者来源标本中，治疗前获得的肿瘤相关内皮细胞表达DR，但在已获得化疗耐药性的SCLC肿瘤中DR表达下调。对化疗耐药标本进行DR激动剂治疗可恢复DR的表达。因此，激活多巴胺信号传导是抑制SCLC血管生成以及潜在对抗化疗难治性SCLC进展的一种新策略。
