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Combined Menin and EGFR Inhibitors Synergize to Suppress Colorectal Cancer via EGFR-Independent and Calcium-Mediated Repression of SKP2 Transcription
Journal article   Open access   Peer reviewed

Combined Menin and EGFR Inhibitors Synergize to Suppress Colorectal Cancer via EGFR-Independent and Calcium-Mediated Repression of SKP2 Transcription

Bryson W Katona, Rebecca A Glynn, Kayla E Paulosky, Zijie Feng, Caroline I Davis, Jian Ma, Corbett T Berry, Katherine M Szigety, Smita Matkar, Yuanyuan Liu, …
Cancer research (Chicago, Ill.), v 79(9), pp 2195-2207
01 May 2019
DOI: https://doi.org/10.1158/0008-5472.CAN-18-2133
PMID: 30877106
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://cancerres.aacrjournals.org/content/canres/79/9/2195.full.pdfView
Published, Version of Record (VoR) Open
url
https://doi.org/10.1158/0008-5472.CAN-18-2133View
Published, Version of Record (VoR) Open

Abstract

Animals Apoptosis Biomarkers, Tumor - genetics Biomarkers, Tumor - metabolism Calcium - metabolism Cell Proliferation Colorectal Neoplasms - drug therapy Colorectal Neoplasms - metabolism Colorectal Neoplasms - pathology Drug Synergism Drug Therapy, Combination Enzyme Inhibitors - pharmacology ErbB Receptors - antagonists & inhibitors ErbB Receptors - genetics ErbB Receptors - metabolism Female Gefitinib - pharmacology Gene Expression Regulation, Neoplastic - drug effects Humans Inositol 1,4,5-Trisphosphate Receptors - genetics Inositol 1,4,5-Trisphosphate Receptors - metabolism Mice Mice, Nude Protein Kinase Inhibitors - pharmacology Proto-Oncogene Proteins - antagonists & inhibitors Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins - metabolism S-Phase Kinase-Associated Proteins - antagonists & inhibitors S-Phase Kinase-Associated Proteins - genetics S-Phase Kinase-Associated Proteins - metabolism Thapsigargin - pharmacology Tumor Cells, Cultured Xenograft Model Antitumor Assays
Menin is a nuclear epigenetic regulator that can both promote and suppress tumor growth in a highly tissue-specific manner. The role of menin in colorectal cancer, however, remains unclear. Here, we demonstrate that menin was overexpressed in colorectal cancer and that inhibition of menin synergized with small-molecule inhibitors of EGFR (iEGFR) to suppress colorectal cancer cells and tumor xenografts in an EGFR-independent manner. Mechanistically, menin bound the promoter of SKP2, a pro-oncogenic gene crucial for colorectal cancer growth, and promoted its expression. Moreover, the iEGFR gefitinib activated endoplasmic reticulum calcium channel inositol trisphosphate receptor 3 (IP3R3)-mediated release of calcium, which directly bound menin. Combined inhibition of menin and iEGFR-induced calcium release synergistically suppressed menin-mediated expression of SKP2 and growth of colorectal cancer. Together, these findings uncover a molecular convergence of menin and the iEGFR-induced, IP3R3-mediated calcium release on SKP2 transcription and reveal opportunities to enhance iEGFR efficacy to improve treatments for colorectal cancer. SIGNIFICANCE: Menin acts as a calcium-responsive regulator of SKP2 expression, and small molecule EGFR inhibitors, which induce calcium release, synergize with Menin inhibition to reduce SKP2 expression and suppress colorectal cancer.

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UN Sustainable Development Goals (SDGs)

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Web of Science research areas
Oncology
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