Inhibition of the transcriptional kinase CDK7 overcomes therapeutic resistance in HER2-positive breast cancers
Authors: Thomas M Roberts
Elizabeth S Yeh
Meixiang Yang
Seth Mason
Qi Wang
Starr E Hazard
Jean J Zhao
Qiwei Wang
Rong Fang
Robert C Wilson
Bowen Sun
Yubao Wang
Journal: Oncogene (2020)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Breast cancer; HER2 inhibitors; kinome reprogramming; HER2/HER3 signaling; tyrosine kinases
Affiliations: The First Affiliated Hospital, Biomedical Translational Research Institute and School of Pharmacy, Jinan University, Guangzhou, 510632, China., Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, 29425, USA., Computational Biology Resource Center, Medical University of South Carolina, Charleston, SC, 29425, USA., Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA., Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA., Department of Pathology, Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, 315211, China., Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, 29425, USA., Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, 29425, USA. .

Abstract:  Resistance of breast cancer to human epidermal growth factor receptor 2 (HER2) inhibitors involves reprogramming of the kinome through HER2/HER3 signaling via the activation of multiple tyrosine kinases and transcriptional upregulation. The heterogeneity of induced kinases prevents kinase targeting by a single kinase inhibitor and presents a major challenge to the treatment of therapeutically recalcitrant HER2-positive breast cancers (HER2+ BCs). As a result, there is a critical need for effective treatment that attacks the aberrant kinome activation associated with resistance to HER2-targeted therapy. Here, we describe a novel treatment strategy that targets cyclin-dependent kinase 7 (CDK7) in HER2 inhibitor-resistant (HER2iR) breast cancer. We show that both HER2 inhibitor-sensitive (HER2iS) and HER2iR breast cancer cell lines exhibit high sensitivity to THZ1, a newly identified covalent inhibitor of the transcription regulatory kinase CDK7. CDK7 promotes cell cycle progression through inhibition of transcription, rather than via direct phosphorylation of classical CDK targets. The transcriptional kinase activity of CDK7 is regulated by HER2, and by the receptor tyrosine kinases activated in response to HER2 inhibition, as well as by the downstream SHP2 and PI3K/AKT pathways. A low dose of THZ1 displayed potent synergy with the HER2 inhibitor lapatinib in HER2iR BC cells in vitro. Dual HER2 and CDK7 inhibition induced tumor regression in two HER2iR BC xenograft models in vivo. Our data support the utilization of CDK7 inhibition as an additional therapeutic avenue that blocks the activation of genes engaged by multiple HER2iR kinases. 

Retracted: No

PubPeer comments:
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