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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.

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.

SUBMITTER: Solberg NT

PROVIDER: S-EPMC6406699 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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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.

Solberg Nina Therese NT Melheim Maria M Strand Martin Frank MF Olsen Petter Angell PA Krauss Stefan S

Cancers 20190201 2

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 loo ...[more]

PMID: 30717152

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