EphA2 inhibition suppresses proliferation of small-cell lung cancer cells through inducing cell cycle arrest

• Published in: Biochemical and biophysical research communications 2019-11, Vol.519 (4), p.846-853
• Main Authors: Ishigaki, Hirotoshi, Minami, Toshiyuki, Morimura, Osamu, Kitai, Hidemi, Horio, Daisuke, Koda, Yuichi, Fujimoto, Eriko, Negi, Yoshiki, Nakajima, Yasuhiro, Niki, Maiko, Kanemura, Shingo, Shibata, Eisuke, Mikami, Koji, Takahashi, Ryo, Yokoi, Takashi, Kuribayashi, Kozo, Kijima, Takashi
• Format: Article
• Language: English
• Subjects: Cell cycle arrest; EphA2; Molecular-targeted therapy; Small-cell lung cancer
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2019.09.076

Small-cell lung cancer (SCLC) is characterized by one of neuroendocrine tumors, and is a clinically aggressive cancer due to its rapid growth, early dissemination, and rapid acquisition of multidrug resistance to chemotherapy. Moreover, the standard chemotherapeutic regimen in SCLC has not changed for three decades despite of the dramatic therapeutic improvement in non-SCLC. The development of a novel therapeutic strategy for SCLC has become a pressing issue. We found that expression of Eph receptor A2 (EphA2) is upregulated in three of 13 SCLC cell lines and five of 76 SCLC tumor samples. Genetic inhibition using siRNA of EphA2 significantly suppressed the cellular proliferation via induction of cell cycle arrest in SBC-5 cells. Furthermore, small molecule inhibitors of EphA2 (ALW–II–41-27 and dasatinib) also exclusively inhibited proliferation of EphA2-positive SCLC cells by the same mechanism. Collectively, EphA2 could be a promising candidate as a therapeutic target for SCLC. •Prognosis of SCLC remains poor over 30 years and targetable oncogenes are yet to be discovered.•EphA2 is a unique RTK which transactivates other growth factor receptors as a ‘hub’ receptor.•EphA2 is overexpressed in a subset of SCLC cell lines and clinical samples.•EphA2 inhibition shows antitumor effects on EphA2-positive SCLC via induction of cell cycle arrest.•EphA2-targeting is promising as a novel molecular targeted therapy in SCLC.