CDK12 drives breast tumor initiation and trastuzumab resistance via WNT and IRS1-ErbB-PI3K signaling.
Hee-Joo ChoiSora JinHani ChoHee-Young WonHee Woon AnGa-Young JeongYoung-Un ParkHyung-Yong KimMi Kyung ParkTaekwon SonKyueng Whan MinKi-Seok JangYoung-Ha OhJeong-Yeon LeeGu KongPublished in: EMBO reports (2019)
Cyclin-dependent kinase 12 (CDK12) has emerged as an effective therapeutic target due to its ability to regulate DNA damage repair in human cancers, but little is known about the role of CDK12 in driving tumorigenesis. Here, we demonstrate that CDK12 promotes tumor initiation as a novel regulator of cancer stem cells (CSCs) and induces anti-HER2 therapy resistance in human breast cancer. High CDK12 expression caused by concurrent amplification of CDK12 and HER2 in breast cancer patients is associated with disease recurrence and poor survival. CDK12 induces self-renewal of breast CSCs and in vivo tumor-initiating ability, and also reduces susceptibility to trastuzumab. Furthermore, CDK12 kinase activity inhibition facilitates anticancer efficacy of trastuzumab in HER2+ tumors, and mice bearing trastuzumab-resistant HER2+ tumor show sensitivity to an inhibitor of CDK12. Mechanistically, the catalytic activity of CDK12 is required for the expression of genes involved in the activation of ErbB-PI3K-AKT or WNT-signaling cascades. These results suggest that CDK12 is a major oncogenic driver and an actionable target for HER2+ breast cancer to replace or augment current anti-HER2 therapies.
Keyphrases
- cell cycle
- cell proliferation
- dna damage
- epidermal growth factor receptor
- pi k akt
- cancer stem cells
- endothelial cells
- tyrosine kinase
- signaling pathway
- oxidative stress
- stem cells
- squamous cell carcinoma
- metastatic breast cancer
- type diabetes
- long non coding rna
- induced pluripotent stem cells
- young adults
- label free