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

• Published in: Cancer research (Chicago, Ill.) Vol. 79; no. 9; pp. 2195 - 2207
• Main Authors: Katona, Bryson W, Glynn, Rebecca A, Paulosky, Kayla E, Feng, Zijie, Davis, Caroline I, Ma, Jian, Berry, Corbett T, Szigety, Katherine M, Matkar, Smita, Liu, Yuanyuan, Wang, Haoren, Wu, Yuan, He, Xin, Freedman, Bruce D, Brady, Donita C, Hua, Xianxin
• Format: Journal Article
• Language: English
• Published: United States 01-05-2019
• Subjects: 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
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-18-2133

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.