Journal Article

Inhibition of CDK8/19 Mediator kinase potentiates HER2-targeting drugs and bypasses resistance to these agents in vitro and in vivo

Ding, Xiaokai, O’Donovan, Norma, Mack, Zachary T., Crown, John, Roninson, Igor B., Zhang, Li, Shtutman, Michael, Li, Jing, Chen, Mengqian, Broude, Eugenia V., McDermott, Martina S. J., Sharko, Amanda C., Ivers, Laura, Chumanevich, Alexander, Ji, Hao, Sikirzhytski, Vitali, Schools, Gary P., Györffy, Balázs

2022

Overview

Breast cancers (BrCas) that overexpress oncogenic tyrosine kinase receptor HER2 are treated with HER2-targeting antibodies (such as trastuzumab) or small-molecule kinase inhibitors (such as lapatinib). However, most patients with metastatic HER2⁺ BrCa have intrinsic resistance and nearly all eventually become resistant to HER2-targeting therapy. Resistance to HER2-targeting drugs frequently involves transcriptional reprogramming associated with constitutive activation of different signaling pathways. We have investigated the role of CDK8/19 Mediator kinase, a regulator of transcriptional reprogramming, in the response of HER2⁺ BrCa to HER2-targeting drugs. CDK8 was in the top 1% of all genes ranked by correlation with shorter relapse-free survival among treated HER2⁺ BrCa patients. Selective CDK8/19 inhibitors (senexin B and SNX631) showed synergistic interactions with lapatinib and trastuzumab in a panel of HER2⁺ BrCa cell lines, overcoming and preventing resistance to HER2-targeting drugs. The synergistic effects were mediated in part through the PI3K/AKT/mTOR pathway and reduced by PI3K inhibition. Combination of HER2- and CDK8/19-targeting agents inhibited STAT1 and STAT3 phosphorylation at S727 and upregulated tumor suppressor BTG2. The growth of xenograft tumors formed by lapatinib-sensitive or -resistant HER2⁺ breast cancer cells was partially inhibited by SNX631 alone and strongly suppressed by the combination of SNX631 and lapatinib, overcoming lapatinib resistance. These effects were associated with decreased tumor cell proliferation and altered recruitment of stromal components to the xenograft tumors. These results suggest potential clinical benefit of combining HER2- and CDK8/19-targeting drugs in the treatment of metastatic HER2⁺ BrCa.

• Publisher: National Academy of Sciences
• Subject: 1-Phosphatidylinositol 3-kinase / AKT protein / Animals / Antibodies / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Biological Sciences / Breast cancer / Breast Neoplasms - drug therapy / Breast Neoplasms - pathology / BTG2 protein / Cell Line, Tumor / Cell proliferation / Cyclin-Dependent Kinase 8 - genetics / Cyclin-Dependent Kinase 8 - metabolism / Cyclin-Dependent Kinases - metabolism / Drug delivery / Drug resistance / Drug Resistance, Neoplasm - drug effects / Drug Resistance, Neoplasm - genetics / Drugs / ErbB-2 protein / Female / Humans / Kinases / Lapatinib - pharmacology / Medical Sciences / Metastases / Metastasis / Mice / Patients / Phosphatidylinositol 3-Kinases - metabolism / Phosphorylation / Protein Kinase Inhibitors - pharmacology / Protein Kinase Inhibitors - therapeutic use / Protein-tyrosine kinase receptors / Receptor, ErbB-2 - metabolism / Stat1 protein / Stat3 protein / Synergistic effect / TOR protein / Trastuzumab / Trastuzumab - metabolism / Trastuzumab - pharmacology / Tumor suppressor genes / Tumors / Tyrosine / Xenograft Model Antitumor Assays / Xenografts / Xenotransplantation