Work

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

Year: 2024

Type: preprint

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 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 chemoresistant 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.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.1101/2024.11.07.622543