Abstract 6572: Screening of drug library targeting neural signaling identifies cholecystokinin B receptor as a potential therapeutic target in small cell lung cancer
Authors: Masakatsu Tokunaga, Natsuki Nakagawa, Mirei Ka, Yuriko Sugiura, Takahiro Iida, Takahiro Ando, Kousuke Watanabe, Hidenori Kage, Masanori Kawakami
Journal: Cancer Research (2024)

Abstract Small cell lung cancer (SCLC) is characterized by poor prognosis with limited therapeutic agents. Development of a new therapeutic strategy is urgently needed. SCLC can be classified into subtypes based on the expression levels of four transcription factors: ASCL1, NEUROD1, POU2F3, and YAP1 (SCLC-A, SCLC-N, SCLC-P, and SCLC-Y, respectively). SCLC-A and SCLC-N are neuroendocrine (NE)-type tumors that secrete neurotransmitters and express their receptors. Recently, neural activity has been noted as a key regulator of cancer growth that affects cancer and other cells in the tumor microenvironment. We hypothesized that neurotransmitters that regulate the biology of NE-type SCLC (SCLC-A, SCLC-N) can be therapeutic targets. To explore this, we created a drug library consisting of 560 drugs known to target neural signaling including various G protein-coupled receptors and examined their growth-inhibitory effects in SCLC cell lines. When three NE-type SCLC cell lines (NCI-H146, SHP-77, and NCI-H446) were treated with 10 μM of the drugs as the first screening, 56 drugs in the library exhibited more than 50% inhibition of cell growth. After excluding drugs with possible nonspecific effects, the IC50 values of 24 drugs were examined in an expanded panel of 20 SCLC cell lines (7 of SCLC-A, 5 of SCLC-N, 3 of SCLC-P, and 5 of SCLC-Y cell lines) as the second screening. Sograzepide, a cholecystokinin B receptor (CCKBR) inhibitor exhibited distinctly lower IC50s in NE-type SCLC cells relative to non-NE-type cells, suggesting that CCKBR is potentially a specific therapeutic target for NE-type SCLC. CCK plays roles both as a neuropeptide in the central nervous system and as a peptide hormone in the gut. In our in silico analysis, CCKBR expression was high in the brain and the stomach, but not detectable in the lung when normal tissues were analyzed with NCBI database. Interestingly, when cancer cells were analyzed with CCLE database, CCKBR expression was substantially high in NE-type SCLC cells, compared with other cancer cells. Furthermore, we found that the growth-inhibitory effects of sograzepide examined in the drug screening were correlated with CCKBR expression levels. Then, we conducted functional analysis of CCKBR in NE-type SCLC cell lines with high CCKBR expression: NCI-H146 (SCLC-A), H209 (SCLC-A), and H524 (SCLC-N) cells. Knockdown of CCKBR by siRNAs inhibited cell proliferation and induced apoptosis. When treated with sograzepide, apoptosis was induced dose-dependently, and cell cycle assays showed increase in sub G1 phase in these cells. Collectively, we identified CCKBR as a potential therapeutic target in NE-type SCLC through screening of drug library targeting neural signaling. Further studies are warranted to reveal the mechanism for antineoplastic effects of antagonizing this neuropeptide receptor in SCLC. Citation Format: Masakatsu Tokunaga, Natsuki Nakagawa, Mirei Ka, Yuriko Sugiura, Takahiro Iida, Takahiro Ando, Kousuke Watanabe, Hidenori Kage, Masanori Kawakami. Screening of drug library targeting neural signaling identifies cholecystokinin B receptor as a potential therapeutic target in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6572.