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Ref Type Journal Article
PMID (30944457)
Authors Moon JH, Hong SW, Kim JE, Shin JS, Kim JS, Jung SA, Ha SH, Lee S, Kim J, Lee DH, Park YS, Kim DM, Park SS, Hong JK, Kim DY, Kim EH, Jung J, Kim MJ, Kim SM, Deming DA, Kim K, Kim TW, Jin DH
Title Targeting β-catenin overcomes MEK inhibition resistance in colon cancer with KRAS and PIK3CA mutations.
Journal Vol Issue Date Pages Journal Short Title
British journal of cancer 120 9 2019 04 941-951 Br J Cancer
URL
Abstract Text 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.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.We identified β-catenin, a key mediator of the WNT pathway, in response to MEK inhibitor. MEK inhibition led to a decrease in β-catenin in PIK3CA wt colon cancer cells but not in mt. Tumour regression was promoted by combination of MEK inhibition and NVP-TNS656, which targets the WNT pathway. Furthermore, inhibition of MEK promoted tumour regression in colon cancer patient-derived xenograft models expressing PIK3CA wt.We propose that inhibition of the WNT pathway, particularly β-catenin, may bypass resistance to MEK inhibition in human PIK3CA mt colon cancer. Therefore, we suggest that β-catenin is a potential predictive marker of MEK inhibitor resistance.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
NVP-TNKS656 NVP-TNKS656 2 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
NVP-TNKS656 NVP656 Tankyrase Inhibitor 11 NVP-TNKS656 is a small molecule that inhibits Tankyrase, resulting in decreased Beta-catenin signaling, and potentially leading to reduced tumor growth (PMID: 26224873, PMID: 30944457, PMID: 31897238).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References