Abstract 4747: Dopamine receptor D2 and dopamine antagonism modulate the progression of small cell lung cancer

Abstract Small cell lung cancer (SCLC) is an aggressive neuroendocrine (NE) cancer and is one of the most lethal types of solid tumors. Although platinum-based therapy forms the backbone of systemic therapy for SCLC, resistance, and recurrence occur rapidly, and most patients die within a year of diagnosis. Despite the approval of immune checkpoint inhibitors for SCLC, the survival benefit of these combinations in an unselected patient population is modest. The majority of SCLCs (∼70-75%) are initiated from pulmonary NE cells; therefore, exploiting NE drivers/modulators is crucial for developing effective therapeutic strategies. To identify novel therapeutic molecules, we performed unbiased RNA-seq expression analysis of NE modulators in SCLC gene expression datasets. Our data showed an atypical expression profile of dopamine receptor D2 (DRD2) in various cell lines of SCLC belonging to NE, non-neuroendocrine, brain metastatic (BrM), and chemotherapy-resistant phenotypes. DRD2 is a G-protein coupled receptor that governs multiple physiological functions, including modulation of the synthesis, storage, and secretion of dopamine (DA); and seems to play a role in neuropsychiatric disorders, brain tumors, and promotes oncogenesis. We studied the role of DRD2 in cell lines representing multiple subtypes of SCLC and tumor tissues compared to their matched normal controls. DRD2 expression was also high in murine SCLC cell lines derived from RPM (Rb1flox/flox; TP53flox/flox; LSL-MycT58A), a spontaneous SCLC mouse model. High expression both in murine and human cell lines derived from brain metastatic lesions (BrM), suggests that DRD2 expression may play an essential role in brain metastasis. Additionally, a substantially high expression of DRD2 was observed in chemotherapy- and immunotherapy-resistant cell lines derived from SCLC patient-derived xenografts. To assess the therapeutic potential of DRD2, we utilized ONC206, a highly specific, orally bioavailable, and blood-brain barrier penetrating DRD2 antagonist. ONC206 treatment attenuated SCLC growth and metastasis, including brain metastasis both in preclinical in vitro and in vivo models. Integrated gene expression studies coupled with pathway analysis showed that DRD2 inhibition reduces SCLC growth and metastasis by inhibiting the cholesterol biosynthesis pathway. Altogether, our study provides strong preclinical rationale for targeting DRD2 via dopamine antagonism to attenuate SCLC growth and metastasis. Citation Format: Parvez Khan, Aatiya Ahmad, Md Arafat Khan, Mahek Fatima, Asad Ur Rehman, Laiba Anwar, Sanib Chaudhary, Imayavaramban Lakshmanan, Anish Thomas, Surinder K. Batra, Varun V. Prabhu, Apar K. Ganti, Mohd Wasim Nasser. Dopamine receptor D2 and dopamine antagonism modulate the progression of small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4747.