Abstract 4745: Comprehensive screening of drugs targeting neural signaling identifies a neuropeptide receptor as a potential therapeutic target in small cell lung cancer

Small cell lung cancer (SCLC) is characterized by poor prognosis with limited therapeutic agents. SCLC can be classified into subtypes based on the expression levels of four transcription factors: ASCL1, NEUROD1, POU2F3, and YAP1. The former two subtypes are neuroendocrine (NE)-type tumors. Recently, neural activity has been noted as a key regulator in the field of oncology. We hypothesized that some neurotransmitters and their receptors can be therapeutic targets regulating the biology of NE-type SCLC. We created a drug library consisting of 560 drugs known to target various neural signaling and examined their growth-inhibitory effects comprehensively on SCLC cells. From this library, 56 drugs exhibited more than 50% inhibition of growth of NE-type SCLC cell lines at 10 μM. After excluding drugs with possible nonspecific effects, the IC50 values of 24 drugs were examined in an expanded panel of SCLC cell lines including non-NE-type cells. The inhibitor of neuropeptide receptor X exhibited distinctly lower IC50s in NE-type SCLC cells relative to non-NE-type cells, suggesting that this receptor is potentially a specific therapeutic target for NE-type SCLC. Neuropeptide receptor X expression was high in the brain but not detectable in the lung when normal tissues were analyzed in silico with NCBI database. Interestingly, when cancer cells were analyzed with CCLE database, this receptor expression was substantially high in NE-type SCLC cells, compared with other cancer cells. Furthermore, the growth-inhibitory effects of the receptor X inhibitor shown in the drug screening were correlated with receptor X expression levels. Using multiple NE-type SCLC cell lines with high receptor X expression, knockdown/knockout of this receptor by siRNAs and CRISPR/Cas9 inhibited cell proliferation. Furthermore, addition of the ligand for receptor X promoted cell proliferation of NE-type SCLC cells, suggesting the significance of signaling by this neuropeptide receptor for NE-type SCLC. Inhibition of receptor X also induced apoptosis in these NE-type SCLC cells, and cell cycle assays showed an increase in sub G1 phase. These effects were not seen in non-NE-type cells. Phospho-protein array analysis followed by Gene Ontology analysis after treatment with the receptor X inhibitor suggested that MAPK and PI3K-Akt signaling pathways were involved in the antineoplastic effects of this inhibitor. Finally, in vivo effects of the receptor X inhibitor were examined in NCI-H146 (NE-type SCLC) xenograft mouse model. The receptor X inhibitor was well tolerated and suppressed the in vivo tumor growth statistically significantly. Collectively, we identified one of the neuropeptide receptors as a potential therapeutic target for NE-type SCLC. This finding warrants further exploration to establish the novel therapeutic strategy for SCLC by targeting neural signaling. Citation Format: Masakatsu Tokunaga, Natsuki Nakagawa, Mirei Ka, Yuriko Sugiura, Takahiro Iida, Hiroaki Ikushima, Takahiro Ando, Kousuke Watanabe, Akiko Kunita, Hidenori Kage, Masanori Kawakami. Comprehensive screening of drugs targeting neural signaling identifies a neuropeptide receptor as a potential therapeutic target in 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 4745.