Abstract
Abstract One of every five breast cancers are driven by gene amplification and overexpression of HER2/ERBB2 tyrosine kinase. HER2+ breast cancers are treated both by monoclonal antibodies (such as trastuzumab) and small-molecule HER2 kinase inhibitors (such as lapatinib). However, some HER2+ tumors are inherently resistant to HER2-targeting drugs and most of metastatic cancers treated with such drugs eventually acquire resistance. We have analyzed the effect of small-molecule inhibitors of transcriptional serine/threonine kinases CDK8 and CDK19, paralogs of the Mediator kinase that modulates the activity of several signal-responsive transcription factors, on the response to lapatinib in a panel of HER2+ breast cancer cell lines. Selective CDK8/19 inhibitors senexin B and SNX631 showed in vitro synergy with lapatinib in different lapatinib-responsive cell lines and overcame lapatinib resistance in cells with either inherent or acquired resistance to this drug. In vivo treatment with SNX631 significantly inhibited the growth of cell-line based and a patient-derived xenograft (PDX) models of HER2+ breast cancer. A combination of SNX631 and lapatinib drastically suppressed the growth of tumors formed by lapatinib-sensitive HCC1954 cells and their lapatinib-resistant derivative HCC1954-L, overcoming lapatinib resistance of the latter. GSEA analysis of RNA-Seq data from cell treated in vitro with lapatinib, senexin B or their combination, showed that lapatinib activated the JAK/STAT pathway but the addition of the CDK8/19 inhibitor suppressed such induction. CDK8/19 inhibitors, when combined with lapatinib, suppressed STAT3 and STAT1 phosphorylation at Ser727. CRISPR/CAS9 knockout of STAT1 and STAT3 together (but not individually) sensitized HER2+ breast cancer cells to lapatinib and reduced the lapatinib-sensitizing effect of CDK8/19 inhibitors, suggesting that STAT1 and STAT3 mediate the effect of CDK8/19. Through miRNA-Seq and QPCR analysis, we have also identified two miRNAs that are regulated by STAT1 or STAT3 and overexpressed in lapatinib-resistant cells. These miRNAs are upregulated upon lapatinib treatment, whereas the combination of lapatinib with senexin B decreases their expression, suggesting that these miRNAs may mediate the effects of CDK8/19 and STAT1/3 on lapatinib resistance. Our results suggest that combining HER2- and CDK8/19-targeting drugs could be a promising therapeutic direction for HER2+ breast cancers after the failure of HER2-targeted therapy. Citation Format: Xiaokai Ding, Amanda C. Sharko, Martina S-J McDermott, Hao Ji, Alexander Chumanevich, Gary P. Schools, Zachary T. Mack, Elena Pugacheva, Victor Tatarskiy, Anastasia Khrustaleva, Alexander Tyakht, Michael Shtutman, Mengqian Chen, Igor Roninson, Eugenia V. Broude. CDK8/19 inhibition overcomes in vitro and in vivo resistance to lapatinib in HER2+ breast cancer via STAT1 and STAT3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB132.
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