A novel PI3K inhibitor iMDK suppresses non-small cell lung Cancer cooperatively with A MEK inhibitor

作者：Ishida Naomasa; Fukazawa Takuya^*; Maeda Yutaka; Yamatsuji Tomoki; Kato Katsuya; Matsumoto Kenichi; Shimo Tsuyoshi; Takigawa Nagio; Whitsett Jeffrey A; Naomoto Yoshio

来源：Experimental Cell Research, 2015, 335(2): 197-206.

DOI：10.1016/j.yexcr.2015.03.019

• PI3K
• MEK
• NSCLC

The PI3K-ART pathway is expected to be a therapeutic target for non-small cell lung cancer (NSCLC) treatment We previously reported that a novel PI3K inhibitor IMDK suppressed NSCLC cells in vitro and in vivo without harming normal cells and mice. Unexpectedly, iMDK activated the MAPK pathway, including ERK, in the NSCLC cells. Since iMDK did not eradicate such NSCLC cells completely, it is possible that the activated MAPK pathway confers resistance to the NSCLC cells against cell death induced by iMDK In the present study, we assessed whether suppressing of iMDK-mediated activation of the MAPK pathway would enhance anti-tumorigenic activity of iMDK. PD0325901, a NIAPK inhibitor, suppressed the MAPK pathway induced by iMDK and cooperatively inhibited cell viability and colony formation of NSCLC cells by inducing apoptosis in vitro. HUVEC tube formation, representing angiogenic processes in vitro, was also cooperatively inhibited by the combinatorial treatment of iMDK and PD0325901. The combinatorial treatment of iMDK with PD0325901 cooperatively suppressed tumor growth and tumor-associated angiogenesis in a lung cancer xenograft model in vivo.

• 出版日期2015-7-15