Author: Gyorffy, Balazs ; Zi, Xiaolin ; Porter, Donald C ; McInnes, Campbell ; Zhang, Li ; Schools, Gary P ; Ding, Xiaokai ; Liang, Jiaxin ; Lilly, Michael B ; Cheng, Chen ; Dowling, Charles E ; Li, Jing ; Chen, Mengqian ; Ji, Hao ; Chumanevich, Alexander A ; Wang, Lili ; Roninson, Igor B ; Broude, Eugenia V ; Liu, Yueying ; Wilding, George ; Sikirzhytski, Vitali ; Lim, Chang-Uk ; Hilimire, Thomas A ; Kerr, Kendall R ; Mack, Zachary T ; Ellis, Leigh

Mediator kinases CDK19 and CDK8, pleiotropic regulators of transcriptional reprogramming, are differentially regulated by androgen signaling, but both kinases are upregulated in castration-resistant prostate cancer (CRPC). Genetic or pharmacological inhibition of CDK8 and CDK19 reverses the castration-resistant phenotype and restores the sensitivity of CRPC xenografts to androgen deprivation in vivo. Prolonged CDK8/19 inhibitor treatment combined with castration not only suppressed the growth of CRPC xenografts but also induced tumor regression and cures. Transcriptomic analysis revealed that Mediator kinase inhibition amplified and modulated the effects of castration on gene expression, disrupting CRPC adaptation to androgen deprivation. Mediator kinase inactivation in tumor cells also affected stromal gene expression, indicating that Mediator kinase activity in CRPC molded the tumor microenvironment. The combination of castration and Mediator kinase inhibition downregulated the MYC pathway, and Mediator kinase inhibition suppressed a MYC-driven CRPC tumor model even without castration. CDK8/19 inhibitors showed efficacy in patient-derived xenograft models of CRPC, and a gene signature of Mediator kinase activity correlated with tumor progression and overall survival in clinical samples of metastatic CRPC. These results indicate that Mediator kinases mediated androgen-independent in vivo growth of CRPC, supporting the development of CDK8/19 inhibitors for the treatment of this presently incurable disease.

04 Mar 2024·Cancer Research

Abstract B058: Targeting mediator kinase CDK8/19 potentiates chemotherapeutic responses, reverses tumor growth, and prolongs survival from ovarian clear cell carcinoma

Author: Mack, Zachary ; School, Gary ; Rangavajhula, Karthik ; Barton, Wade ; Chen, Mengqian ; Broude, Eugenia V. ; Arend, Rebecca ; Kumari, Asha ; Mythreye, Karthikeyan ; Quintero, Liz Macias

AbstractOvarian clear cell carcinomas (OCCC) are a rare histological subtype of epithelial ovarian cancer with known treatment resistance, a feature associated with transcriptional reprogramming. CDK8 and CDK19 Mediator Kinases, which are isoforms of the Mediator Kinase – enzymatic components of a regulatory module that binds to the transcriptional Mediator complex –and not a part of the overall transcription machinery, have been previously reported to modify oncogenic transcription factors. Inhibition of the kinase activity of CDK8/19 was shown to prevent and reverse chemoresistance in other cancers with two CDK8/19 inhibitors currently in clinical trials for non–ovarian cancers. Based on the unmet need for OCCCs, we assessed CDK8/19 expression in a panel of OCCC primary and metastatic tissues and utilized cell line models for investigation into the therapeutic potential of CDK8/19 inhibitors in preventing tumorigenesis and synergizing with existing chemotherapeutics. The synergistic effects of SNX631-6, a preclinical CDK8/19 inhibitor drug candidate, were tested in vitro using three clear cell (ES2, TOV-21-G, RMG1) and one non-clear cell (SKOV3) ovarian carcinoma cell lines. A sub-inhibitory concentration 50 (IC50) concentration of SNX631-6 (500 nM) strongly potentiated effects of cisplatin, carboplatin, and paclitaxel. Additionally, cells demonstrating platinum resistance reverted to platinum sensitivity when exposed to the same concentration of SNX631-6. In vivo antitumor effects and tolerability of oral SNX631-6 were assessed in Foxn1nu homozygous female mice injected subcutaneously with ES2+luc cells. Mice were treated with a vehicle (n=10), intraperitoneal (IP) cisplatin (2 mg/kg) twice weekly (n=9), SNX631-6 medicated diet (330 ppm) orally ad libitum (n=10), or IP cisplatin combined with SNX631 diet (n=10) until tumors reached a predetermined critical volume of 2500mm3. In ES2+luc injected mice, significant tumor growth inhibition relative to vehicle occurred in mice treated with a combination of IP cisplatin and SNX631-6 (p<0.001) or SNX631-6 alone (p<0.01). Additionally, the use of IP cisplatin and SNX631-6 significantly delayed time-to-critical-volume compared to vehicle (p=0.0001). SNX631-6 alone and in combination with IP cisplatin was well tolerated in all mice based on body weight measurements. In summary, SNX631-6 potentiated platinum responses in vitro and demonstrated strong in vivo antitumor effects, including tumor regression, when used as monotherapy and in combination with platinum-based therapy. These data suggest that therapeutically achievable doses of SNX631-6 may provide clinical benefit, prevent tumorigenesis, and reverse platinum resistance in patients with OCCC.Citation Format: Wade Barton, Asha Kumari, Gary School, Zachary Mack, Liz Macias Quintero, Karthik Rangavajhula, Rebecca Arend, Mengqian Chen, Eugenia V. Broude, Karthikeyan Mythreye. Targeting mediator kinase CDK8/19 potentiates chemotherapeutic responses, reverses tumor growth, and prolongs survival from ovarian clear cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B058.

09 Aug 2022·Proceedings of the National Academy of SciencesQ1 · CROSS-FIELD

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

Q1 · CROSS-FIELD

Article

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

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.

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Drug(Targets)	Indications	Global Highest Phase

Senexin B ( CDK19 x CDK8 )	Breast Cancer More	Preclinical
Senexin A ( CDK19 x CDK8 )	Neoplasms More	Preclinical
COPZ1-targeting coatomer inhibitors(Senex) ( COPZ1 )	Neoplasms More	Preclinical
Senexin C ( CDK19 x CDK8 )	Neoplasms More	Preclinical
SNX-631 ( CDK19 x CDK8 )	Breast Cancer More	Preclinical

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