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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 British journal of cancer
Vol 120
Issue 9
Date 2019 04
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
Drug Name Trade Name Synonyms Drug Classes Drug Description
NVP-TNKS656 NVP656 Tankyrase Inhibitor 10 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
PIK3CA mutant colon cancer predicted - resistant NVP-TNKS656 Preclinical - Cell line xenograft Actionable In a preclinical study, NVP-TNKS656 treatment alone did not significantly inhibit viability of PIK3CA mutant colon cancer cells in culture, and did not inhibit tumor growth in a cell line xenograft model (PMID: 30944457). 30944457
PIK3CA mutant colon cancer predicted - resistant Selumetinib Preclinical - Cell line xenograft Actionable In a preclinical study, Koselugo (selumetinib) treatment did not induce cell death, apoptosis, or inhibit colony formation in PIK3CA mutant colon cancer cells in culture, and did not inhibit tumor growth in a cell line xenograft model (PMID: 30944457). 30944457
CTNNB1 over exp PIK3CA wild-type colon cancer resistant Pimasertib Preclinical - Cell culture Actionable In a preclinical study, overexpression of CTNNB1 in PIK3CA wild-type colon cancer cells suppressed cell death following Pimasertib (MSC1936369B) treatment in culture (PMID: 30944457). 30944457
PIK3CA wild-type colon cancer sensitive Refametinib Preclinical - Cell culture Actionable In a preclinical study, Refametinib (BAY86-9766) treatment inhibited colony formation, and induced cell death and apoptosis in PIK3CA wild-type colon cancer cells in culture (PMID: 30944457). 30944457
PIK3CA mutant colon cancer predicted - resistant Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) treatment did not induce cell death, apoptosis, or inhibit colony formation in PIK3CA mutant colon cancer cells in culture, and did not inhibit tumor growth in a cell line xenograft model (PMID: 30944457). 30944457
CTNNB1 wild-type PIK3CA mut colon cancer predicted - sensitive NVP-TNKS656 + Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) treatment in combination with NVP-TNKS656 induced cell death in colon cancer cells with wild-type CTNNB1 and mutant PIK3CA in culture (PMID: 30944457). 30944457
PIK3CA wild-type colon cancer sensitive Pimasertib Preclinical - Cell culture Actionable In a preclinical study, Pimasertib (MSC1936369B) treatment inhibited colony formation, and induced cell death and apoptosis in PIK3CA wild-type colon cancer cells in culture (PMID: 30944457). 30944457
PIK3CA mutant colon cancer predicted - sensitive NVP-TNKS656 + Trametinib Preclinical - Cell line xenograft Actionable In a preclinical study, Mekinist (trametinib) treatment in combination with NVP-TNKS656 enhanced cell death in PIK3CA mutant colon cancer cells in culture, and induced apoptosis and inhibited tumor growth in a cell line xenograft model (PMID: 30944457). 30944457
CTNNB1 S33Y PIK3CA mut colon cancer resistant NVP-TNKS656 + Trametinib Preclinical - Cell culture Actionable In a preclinical study, PIK3CA mutant colon cancer cells expressing CTNNB1 S33Y demonstrated suppression of cell death following Mekinist (trametinib) and NVP-TNKS656 combination treatment in culture (PMID: 30944457). 30944457
PIK3CA mutant colon cancer predicted - resistant Refametinib Preclinical - Cell culture Actionable In a preclinical study, Refametinib (BAY86-9766) treatment did not induce cell death, apoptosis, or inhibit colony formation in PIK3CA mutant colon cancer cells in culture (PMID: 30944457). 30944457
CTNNB1 wild-type PIK3CA mut colon cancer predicted - sensitive NVP-TNKS656 Preclinical - Cell culture Actionable In a preclinical study, NVP-TNKS656 treatment induced cell death in colon cancer cells with wild-type CTNNB1 and mutant PIK3CA in culture (PMID: 30944457). 30944457
PIK3CA wild-type colon cancer sensitive Selumetinib Preclinical - Cell line xenograft Actionable In a preclinical study, Koselugo (selumetinib) treatment inhibited colony formation, and induced cell death and apoptosis in PIK3CA wild-type colon cancer cells in culture, and reduced tumor growth in a cell line xenograft model (PMID: 30944457). 30944457
CTNNB1 over exp PIK3CA wild-type colon cancer resistant Refametinib Preclinical - Cell culture Actionable In a preclinical study, overexpression of CTNNB1 in PIK3CA wild-type colon cancer cells suppressed cell death following Refametinib (BAY86-9766) treatment in culture (PMID: 30944457). 30944457
PIK3CA mutant colon cancer predicted - resistant Pimasertib Preclinical - Cell culture Actionable In a preclinical study, Pimasertib (MSC1936369B) treatment did not induce cell death, apoptosis, or inhibit colony formation in PIK3CA mutant colon cancer cells in culture (PMID: 30944457). 30944457
CTNNB1 over exp PIK3CA wild-type colon cancer resistant Trametinib Preclinical - Cell culture Actionable In a preclinical study, overexpression of CTNNB1 in PIK3CA wild-type colon cancer cells suppressed cell death following Mekinist (trametinib) treatment in culture (PMID: 30944457). 30944457
CTNNB1 mut PIK3CA mut colon cancer predicted - resistant NVP-TNKS656 + Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) treatment in combination with NVP-TNKS656 did not induce cell death in PIK3CA and CTNNB1 mutant colon cancer cells in culture (PMID: 30944457). 30944457
CTNNB1 mut PIK3CA mut colon cancer predicted - resistant NVP-TNKS656 Preclinical - Cell culture Actionable In a preclinical study, NVP-TNKS656 treatment did not induce cell death in PIK3CA and CTNNB1 mutant colon cancer cells in culture (PMID: 30944457). 30944457
CTNNB1 over exp PIK3CA wild-type colon cancer resistant Selumetinib Preclinical - Cell culture Actionable In a preclinical study, overexpression of CTNNB1 in PIK3CA wild-type colon cancer cells suppressed cell death following Koselugo (selumetinib) treatment in culture (PMID: 30944457). 30944457
PIK3CA wild-type colon cancer sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) treatment inhibited colony formation, and induced cell death and apoptosis in PIK3CA wild-type colon cancer cells in culture (PMID: 30944457). 30944457
PIK3CA mutant colon cancer predicted - sensitive NVP-TNKS656 + Selumetinib Preclinical - Cell culture Actionable In a preclinical study, Koselugo (selumetinib) treatment in combination with NVP-TNKS656 enhanced cell death in PIK3CA mutant colon cancer cells in culture (PMID: 30944457). 30944457