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. 2018 Jun 18;501(1):253-258.
doi: 10.1016/j.bbrc.2018.04.230. Epub 2018 May 5.

Trametinib downregulates survivin expression in RB1-positive KRAS-mutant lung adenocarcinoma cells

Toshiyuki Sumi  1 , Sachie Hirai  2 , Miki Yamaguchi  2 , Yusuke Tanaka  1 , Makoto Tada  3 , Toshiro Niki  4 , Hiroki Takahashi  5 , Yuji Sakuma  6
Affiliations

Trametinib downregulates survivin expression in RB1-positive KRAS-mutant lung adenocarcinoma cells

Toshiyuki Sumi et al. Biochem Biophys Res Commun. .

Abstract

High expression levels of survivin in KRAS-mutant lung adenocarcinomas are linked with unfavorable patient outcomes, suggesting that survivin is a promising target for tumor treatment. We found that trametinib, a MEK inhibitor, downregulates survivin expression in the RB1-positive KRAS-mutant lung adenocarcinoma cell lines H358 and H441. In these cell lines, trametinib treatment induced p21 expression and dephosphorylated RB1, leading to sustained suppression of survivin. Knockdown of p21 or RB1 restored survivin expression in trametinib-treated cells, at least partially, which supports the contribution of these molecules to trametinib-mediated survivin suppression. In RB1-negative KRAS-mutant lung adenocarcinoma H2009 cells, survivin downregulation by trametinib was only slight and transient, and trametinib-resistant (TR) cells developed within 1 month of treatment. H2009 TR cells depended much more on survivin for survival than its parental cells, as evidenced by apoptosis induction when survivin was depleted. These findings collectively suggest that trametinib is effective for the treatment of RB1-positive KRAS-mutant lung adenocarcinomas through sustained survivin suppression, but not for RB1-negative lung adenocarcinomas. Thus, the RB1 status could be a biomarker for trametinib application in KRAS-mutant lung adenocarcinomas.

Keywords: KRAS-mutant lung adenocarcinoma; RB1; Survivin; Trametinib; p21.

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