MEK Inhibition Induces Canonical WNT Signaling through YAP in KRAS Mutated HCT-15 Cells, and a Cancer Preventive FOXO3/FOXM1 Ratio in Combination with TNKS Inhibition.

Nina Solberg,Stefan Krauss,Maria Melheim,Martin Strand,Petter Olsen

doi:10.3390/cancers11020164

Nina Solberg, Stefan Krauss + Show 3 more

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https://doi.org/10.3390/cancers11020164

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Abstract

The majority of colorectal cancers are induced by subsequent mutations in APC and KRAS genes leading to aberrant activation of both canonical WNT and RAS signaling. However, due to induction of feedback rescue mechanisms some cancers do not respond well to targeted inhibitor treatments. In this study we show that the APC and KRAS mutant human colorectal cancer cell line HCT-15 induces canonical WNT signaling through YAP in a MEK dependent mechanism. This inductive loop is disrupted with combined tankyrase (TNKS) and MEK inhibition. RNA sequencing analysis suggests that combined TNKS/MEK inhibition induces metabolic stress responses in HCT-15 cells promoting a positive FOXO3/FOXM1 ratio to reduce antioxidative and cryoprotective systems.

Highlights

IntroductionOf colorectal cancers (CRCs) are induced by loss-of-function mutations in the adenomatous polyposis coli (APC) tumor suppressor gene, followed by nuclear accumulation of the canonical WNT signaling effector β-catenin [2]
Colorectal cancer is the second leading cause of cancer death worldwide (WHO, [1])
It has previously been shown that TNKS inhibition sensitizes KRAS mutant cancer cells to growth inhibition by MEK inhibitors [13], in cell lines whose proliferation rate is unaffected by single

Summary

Introduction

Of colorectal cancers (CRCs) are induced by loss-of-function mutations in the adenomatous polyposis coli (APC) tumor suppressor gene, followed by nuclear accumulation of the canonical WNT signaling effector β-catenin [2]. KRAS mutation in 50% of colorectal cancers [3,4,5]. Neither APC nor KRAS mutations alone induce a colorectal cancer phenotype [6], APC mutations induce RAS activation through inactivation of glycogen synthase kinase 3β (GSK3β) [7]. The GSK3β containing β-catenin destruction complex is stabilized by both APC and axis inhibition protein 1 and 2 (AXIN1/2) in the absence of canonical WNT signals, promoting proteasomal degradation of both β-catenin (reviewed by [8]) and a subset of RAS proteins [7]. Development of TNKS inhibitors has gained increasing attention as a treatment strategy for WNT induced colorectal cancer

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