The PI3Kα inhibitor DFX24 suppresses tumor growth and metastasis in non-small cell lung cancer via ERK inhibition and EPHB6 reactivation

• Published in: Pharmacological research Vol. 160; p. 105147
• Main Authors: Fan, Yan-Hua, Ding, Huai-Wei, Kim, Donghwa, Liu, Jian-Yu, Hong, Ji-Young, Xu, Yong-Nan, Wang, Daoping, Yang, Xiao-Sheng, Lee, Sang Kook
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01.10.2020
• Subjects: Apoptosis; Cell cycle arrest; EPHB6; Non-Small cell lung cancer (NSCLC); PI3Kα inhibitor; quinazolin-4(3H)-one analog(DFX24); EPHB6; quinazolin-4(3H)-one analog(DFX24); Cell cycle arrest; Non-Small cell lung cancer (NSCLC); PI3Kα inhibitor; Apoptosis
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2020.105147

[Display omitted] •EPHB6 inhibited metastasis and activated Akt and ERK in NSCLC.•DFX24 suppressed metastasis by increasing EPHB6 expression.•DFX24 inhibited cell growth via PI3K/Akt and ERK pathway inhibition.•DFX24 promoted apoptosis by activating mitochondria-dependent pathway. EPHB6 is a metastasis inhibitory gene that is frequently decreased or deficiency in non-small cell lung cancer (NSCLC), which contributed to the subsequent development of distant metastasis. These suggested the possibility that reactivation of EPHB6 might prevent the metastasis of NSCLC. Nevertheless, EPHB6 expression might also promote cancer cell growth and inhibit cell apoptosis by activating Akt and ERK pathway, apart from inhibition of migration and invasion. In the present study, we developed a novel quinazolin-4(3H)-one analog (DFX24) as a potential PI3Kα inhibitor, which inhibited both cell proliferation and metastasis of NSCLC cell lines. Investigation to the molecular mechanisms revealed DFX24 inhibited the cell growth and metastasis via inhibition of PI3Kα and ERK activity, as well as the increase in EPHB6 expression. In addition, DFX24 also induced cell cycle arrest and tumor cell apoptosis by inhibiting PI3K/Akt pathway and activating mitochondria-dependent pathway, respectively. These findings suggested that DFX24 might be considered as a novel drug candidate and may provide a potential therapy for NSCLC.