Abstract P5-04-07: CDK8 protein complex as a potential biomarker and therapeutic target in breast cancer
Authors: McDermott MSJ , Györffy B , Chumanevich AA , Kaza V , Porter DC , Catroppo JF , Chen M , Oliver D , Shtutman M , Roninson IB , Broude EV 
Published: May 2016

Abstract
Cyclin-dependent kinase 8 (CDK8) and its paralog CDK19 are transcriptional regulators that, in complex with CCNC, MED12 and MED13, mediate several carcinogenic signalling pathways such as NFκβ, TGFβ/BMP, WNT/β-catenin, HIF1A and serum growth factor network. Using immunohistochemical analysis, we found that CDK8/19 protein is overexpressed in invasive ductal carcinomas of the breast relative to non-malignant mammary tissues. TCGA database analysis showed that gene amplification is the most frequent type of genetic alterations of CDK8, CDK19, CCNC and MED13 in breast cancers, with MED13 appearing as one of the most frequently amplified genes in breast cancer (amplified in 9.7% of samples), whereas point mutations are more common in MED12. CDK8, CDK19 and CCNC expression was strongly increased but MED12 expression was decreased in tumors with mutant p53. Meta-analysis of transcriptome databases revealed that higher expression of CDK8, CDK19, CCNC and MED13 (but not MED12) is associated with shorter relapse-free survival (RFS) in the four molecular subtypes of breast cancer. The RFS correlations were much stronger in patients who underwent systemic adjuvant therapy than in untreated patients, suggesting that CDK8 and its interactive genes impact the failure of systemic therapy. This result is in agreement with the role of CDK8 as a mediator of the chemotherapy-induced paracrine network that promotes drug resistance and metastasis (Porter et al., PNAS, 109, 13799, 2012) and with our finding that a small-molecule CDK8/19 inhibitor augmented the efficacy of doxorubicin in a triple-negative breast cancer xenograft model. The expression levels of CDK8, CDK19, CCNC and MED13 in breast cancer samples were directly correlated with each other and with the expression of MYC but inversely correlated with estrogen receptor (ER)α expression. Since MYC is known to be a positive downstream mediator of the ER activity, we hypothesized that CDK8 may play a similar role, with an increase in CDK8 augmenting estrogen mitogenic signalling in tumors with decreased ER. Confirming this hypothesis, we have found that CDK8 inhibition by selective small-molecule CDK8/19 inhibitors or by shRNA knockdown suppresses estrogen-induced transcription in ER-positive breast cancer cell lines. CDK8/19 inhibition abrogates the mitogenic effect of estrogen on ER-positive cells and synergizes with the ER antagonist fulvestrant. Treatment of estrogen-deprived ER-positive cells with a CDK8/19 inhibitor significantly impeded the outgrowth of estrogen-independent cells, to a greater extent than did mTOR or HER2 targeted drugs. These results indicate that the expression of CDK8 and its interactive genes has a profound impact on the response to treatment in breast cancer and may provide novel biomarkers for relapse-free survival after adjuvant therapy. CDK8/19 inhibition may be useful to augment chemotherapy and hormone therapy of breast cancer and to prevent the development of tumors resistant to estrogen deprivation.
Citation Format: McDermott MSJ, Györffy B, Chumanevich AA, Kaza V, Porter DC, Catroppo JF, Chen M, Oliver D, Shtutman M, Roninson IB, Broude EV. CDK8 protein complex as a potential biomarker and therapeutic target in breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-04-07.