Unknown,Transcriptomics,Genomics,Proteomics

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Targeting β-catenin overcomes resistance to MEK inhibitor in PIK3CA mutant colon cancer

ABSTRACT: Mitogen-activated protein kinases (MEK 1/2) are central components of the RAS signaling pathway and attractive targets for cancer therapy. However, PIK3CA mutation, which commonly co-occurs with KRAS mutation, offered resistance to MEK inhibitor through activation of PI3K-AKT signaling. We identified a gene that cooperates with MEK inhibitors to forcefully treat PIK3CA mutant colon cancer cells. -catenin, a key molecule of the WNT pathway, emerged as a candidate by protein/Ab Chip array. MEK inhibitor treatment led to a decrease in -catenin in PIK3CA wild-type colon cancer cells but not in PIK3CA mutant colon cancer cells. Tumor regression was promoted by a combination of MEK inhibitor and NVP-TNS656, which targets the WNT pathway. Furthermore, combined inhibition of MEK and -catenin by NVP-TNS656 promoted tumor regression in colon cancer patient-derived xenograft (PDX) models expressing mutant PIK3CA. Taken together, we propose that inhibition of the WNT pathway, particularly -catenin, may bypass resistance to MEK inhibitor in human PIK3CA mutant colon cancer. Additionally, -catenin is a potential PD marker of MEK inhibitor resistance. In the study, we identified and evaluated biomarker for response to MEK inhibitor on colon cancer cells.

ORGANISM(S): Homo sapiens

SUBMITTER: Dong-Hoon Jin

PROVIDER: E-GEOD-71981 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:To analyze whether Wnt inhibitors LF3 and ICG-001 have similar influence on the gene expression of mouse salivary gland cancer stem cells Wnt/β-catenin signaling is a system that is essential for embryogenesis and tissue homeostasis which has been highly conserved through evolution. A deregulation of Wnt/β-catenin signals can initiate and promote human cancers, specifically of the colon, head and neck. As such, Wnt/β-catenin signaling represents an attractive target for cancer therapy. So far, however, no rationally developed compound targeting Wnt signaling has found clinical use. The interaction between β-catenin and TCF4 is necessary in the transduction of the signal; here we performed a High-Throughput-Screening (HTS) using AlphaScreen and ELISA techniques to identify small molecules that specifically disrupt this interaction. We identified compound LF3, a 4-thioureido-benzenesulfonamide derivative, as a robust inhibitor of β-catenin/TCF4 interactions and thus a good starting point for drug discovery, as suggested by Lipinski's “rule of five.” LF3 inhibited Wnt/β-catenin signaling in cells with exogenous reporters and in colon cancer cells with endogenously high Wnt activity. Medicinal chemistry identified an essential core structure and residues that could not be modified in LF3. Compound LF3 inhibited a number of features of cancer cells related to Wnt signaling, including high cell motility in Boyden chamber assays, hyperproliferation through induction of cell cycle arrest at the G1 phase, and the overexpression of key Wnt target genes. LF3 does not cause apoptosis or cell death or interfere with cadherin-mediated cell-cell adhesion. Remarkably, the self-renewal capacity of cancer stem cells was blocked by LF3 in concentration-dependent manners, as demonstrated by examination of sphere formation of colon and head and neck cancer stem cells in serum-free, non-attached conditions. LF3 also reduced tumor growth and induced differentiation in colon tumors in mouse xenografts. LF3 is thus a specific inhibitor of canonical Wnt signaling with a significant potential for further development for preclinical and clinical studies in cancer treatment.

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Targeting β-catenin overcomes resistance to MEK inhibitor in PIK3CA mutant colon cancer

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