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
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.