Targeting β-catenin overcomes MEK inhibition resistance in colon cancer with KRAS and PIK3CA mutations.

ABSTRACT:

Background

Mitogen-activated protein kinases (MEK 1/2) are central components of the RAS signalling pathway and are attractive targets for cancer therapy. These agents continue to be investigated in KRAS mutant colon cancer but are met with significant resistance. Clinical investigations have demonstrated that these strategies are not well tolerated by patients.

Methods

We investigated a biomarker of response for MEK inhibition in KRAS mutant colon cancers by LC-MS/MS analysis. We tested the MEK inhibitor in PIK3CA wild(wt) and mutant(mt) colon cancer cells. In addition, we tested the combinational effects of MEK and TNKS inhibitor in vitro and in vivo.

Results

We identified β-catenin, a key mediator of the WNT pathway, in response to MEK inhibitor. MEK inhibition led

SUBMITTER: Moon JH 

PROVIDER: S-EPMC6734664 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature