Abstract
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 D2 receptor (D2R) agonist reduces tumour angiogenesis in multiple in vivo xenograft models of human SCLC, thereby reducing SCLC progression. An FDA-approved D2R agonist, cabergoline, also sensitized chemotherapy-resistant SCLC tumours to cisplatin and etoposide in patient-derived xenograft models of acquired chemoresistance in mice. Ex vivo, D2R 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, D2R was expressed by tumour-associated endothelial cells obtained before treatment, but D2R was downregulated in SCLC tumours that had acquired chemoresistance. D2R agonist treatment of chemotherapy-resistant specimens restored expression of D2R. Activation of dopamine signalling is thus a new strategy for inhibiting angiogenesis in SCLC and potentially for combatting chemotherapy-refractory SCLC progression.