Dopamine D(2) receptor agonists abrogate neuroendocrine tumour angiogenesis to inhibit chemotherapy-refractory small cell lung cancer progression.

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(2) receptor (D(2)R) agonist reduces tumour angiogenesis in multiple in vivo xenograft models of human SCLC, thereby reducing SCLC progression. An FDA-approved D(2)R agonist, cabergoline, also sensitized chemotherapy-resistant SCLC tumours to cisplatin and etoposide in patient-derived xenograft models of acquired chemoresistance in mice. Ex vivo, D(2)R 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, D(2)R was expressed by tumour-associated endothelial cells obtained before treatment, but D(2)R was downregulated in SCLC tumours that had acquired chemoresistance. D(2)R agonist treatment of chemotherapy-resistant specimens restored expression of D(2)R. Activation of dopamine signalling is thus a new strategy for inhibiting angiogenesis in SCLC and potentially for combatting chemotherapy-refractory SCLC progression.