Modulation of host glutamine anabolism enhances the sensitivity of small cell lung cancer to chemotherapy

Manabu Kodama; Gouji Toyokawa; Osamu Sugahara; Shigeaki Sugiyama; Naoki Haratake; Yuichi Yamada; Reona Wada; Shinkichi Takamori; Mototsugu Shimokawa; Tomoyoshi Takenaka; Tetsuzo Tagawa; Hiroki Kittaka; Takeshi Tsuruda; Kentaro Tanaka; Yushiro Komatsu; Keisuke Nakata; Yuri Imado; Koji Yamazaki; Isamu Okamoto; Yoshinao Oda; Masatomo Takahashi; Yoshihiro Izumi; Takeshi Bamba; Hideyuki Shimizu; Tomoharu Yoshizumi; Keiichi I Nakayama

doi:10.1016/j.celrep.2023.112899

Modulation of host glutamine anabolism enhances the sensitivity of small cell lung cancer to chemotherapy

Cell Rep. 2023 Aug 29;42(8):112899. doi: 10.1016/j.celrep.2023.112899. Epub 2023 Aug 1.

Authors

Manabu Kodama¹, Gouji Toyokawa², Osamu Sugahara¹, Shigeaki Sugiyama¹, Naoki Haratake³, Yuichi Yamada⁴, Reona Wada¹, Shinkichi Takamori³, Mototsugu Shimokawa⁵, Tomoyoshi Takenaka³, Tetsuzo Tagawa³, Hiroki Kittaka⁶, Takeshi Tsuruda¹, Kentaro Tanaka⁷, Yushiro Komatsu⁸, Keisuke Nakata⁹, Yuri Imado⁹, Koji Yamazaki¹⁰, Isamu Okamoto⁷, Yoshinao Oda⁴, Masatomo Takahashi⁹, Yoshihiro Izumi⁹, Takeshi Bamba⁹, Hideyuki Shimizu⁸, Tomoharu Yoshizumi³, Keiichi I Nakayama¹¹

Affiliations

¹ Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
² Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Department of Thoracic Surgery, NHO Kyushu Medical Center, 1-8-1 Jigyohama, Chuo-ku, Fukuoka 810-0065, Japan.
³ Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
⁴ Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
⁵ Department of Biostatistics, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi 755-8505, Japan.
⁶ Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; LSI Medience Corporation, 1-13-4 Uchikanda, Chiyoda-ku, Tokyo 101-8517, Japan.
⁷ Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
⁸ Department of AI Systems Medicine, M&D Data Science Center, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan.
⁹ Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
¹⁰ Department of Thoracic Surgery, NHO Kyushu Medical Center, 1-8-1 Jigyohama, Chuo-ku, Fukuoka 810-0065, Japan.
¹¹ Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Anticancer Strategies Laboratory, TMDU Advanced Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. Electronic address: nakayak1@bioreg.kyushu-u.ac.jp.

PMID: 37531252
DOI: 10.1016/j.celrep.2023.112899

Abstract

Small cell lung cancer (SCLC) is one of the deadliest human cancers, with a 5-year survival rate of ∼7%. Here, we performed a targeted proteomics analysis of human SCLC samples and thereby identified hypoxanthine phosphoribosyltransferase 1 (HPRT1) in the salvage purine synthesis pathway as a factor that contributes to SCLC malignancy by promoting cell survival in a glutamine-starved environment. Inhibition of HPRT1 by 6-mercaptopurine (6-MP) in combination with methotrexate (MTX), which blocks the de novo purine synthesis pathway, attenuated the growth of SCLC in mouse xenograft models. Moreover, modulation of host glutamine anabolism with the glutamine synthetase inhibitor methionine sulfoximine (MSO) in combination with 6-MP and MTX treatment resulted in marked tumor suppression and prolongation of host survival. Our results thus suggest that modulation of host glutamine anabolism combined with simultaneous inhibition of the de novo and salvage purine synthesis pathways may be of therapeutic benefit for SCLC.

Keywords: CP: Cancer; HPRT1; host glutamine metabolism; nucleotide biosynthesis; salvage pathway; small cell lung cancer.