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

Abstract

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 up-regulated 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.

Overcoming Resistance to HER2-Directed Therapies in Breast Cancer

“…Another described mechanism of resistance to HER2-targeted agents is transcriptional deregulation via aberrant activation of multiple tyrosine kinases [ 58 , 59 ]. Preclinical models have shown that inhibition of the cyclin-dependent kinases 7 or 8 can restore sensibility to HER2-targeted agents [ 58 , 59 ]. Clinical studies are needed to determine the efficacy and tolerance of these medications in combination with HER2-targeted agents.…”

CDK8/19 Inhibition Attenuates G1 Arrest Induced by BCR-ABL Antagonists and Accelerates Death of Chronic Myelogenous Leukemia Cells

“…SenB potentiated cell death induced not only by IM but also by other BCR-ABL antagonists of different chemical classes and specificity (Figures 2A-B). Furthermore, the synergy with IM was also shown for the second, chemically unrelated CDK8/19i SNX631 (30,44), indicating that the sensitization was a general effect of CDK8/19 inhibition (Figures 2C-D).…”

“…CDK8/19 also directly phosphorylate transcription factors, such as STATs (50). CDK8/19 have been established as druggable antitumor targets, either alone (NCT04021368) or in combination with conventional therapeutics (29,30). Exploring the possibility to improve the efficacy of BCR-ABLi in CML cells, we herein demonstrated that SenB as well as other CDK8/19i sensitized the K562 CML cells to various BCR-ABLi (Figures 2A-D).…”

“…The role of CDK8/19-mediated transcriptional reprogramming in acquired drug resistance was demonstrated by the ability of small-molecule CDK8/19 inhibitors (CDK8/19i) to sensitize tumor cells or to prevent the emergence of resistance to chemotherapeutics including inhibitors of estrogen receptor and EGFRs (28)(29)(30). Thus, CDK8/19i are considered as antitumor drug candidates in combined regimens.…”

Discovery of a Novel and Potent Cyclin-Dependent Kinase 8/19 (CDK8/19) Inhibitor for the Treatment of Cancer

“…The mediator kinase CDK8 and its paralog CDK19 play important roles during cell proliferation and differentiation through regulating signal-induced, context-specific transcription reprogramming. − CDK8, CDK19, and their binding partner cyclin C, are frequently amplified in various tumor types and contribute to tumor growth, cancer metastasis, and give rise to chemoresistance. , Through phosphorylation of transcription factors and the C-terminal domain of RNA polymerase II, CDK8/19 has been shown to activate Wnt/β-catenin signaling in colorectal cancer, to promote growth of estrogen receptor-positive breast cancer, to advance prostate cancer, , and to potentiate oncogenic signaling − and glycolysis . There are numerous studies demonstrating that pharmacological inhibition of the kinase activity of CDK8/CDK19 could suppress cancer cell proliferation, inhibit metastasis, and enhance chemosensitivity in many hematological and solid cancer types, including acute myeloid leukemia (AML), , breast cancer, ,,, colorectal cancer, − and prostate cancer. ,, Thus, CDK8/19 is emerging as a promising target for cancer therapy.…”