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CDK 12 drives breast tumor initiation and trastuzumab resistance via WNT and IRS 1‐ErbB‐ PI 3K signaling
Author(s) -
Choi HeeJoo,
Jin Sora,
Cho Hani,
Won HeeYoung,
An Hee Woon,
Jeong GaYoung,
Park YoungUn,
Kim HyungYong,
Park Mi Kyung,
Son Taekwon,
Min KyuengWhan,
Jang KiSeok,
Oh YoungHa,
Lee JeongYeon,
Kong Gu
Publication year - 2019
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201948058
Subject(s) - trastuzumab , cancer research , wnt signaling pathway , erbb , cyclin dependent kinase , breast cancer , protein kinase b , carcinogenesis , biology , signal transduction , cancer , medicine , cell cycle , microbiology and biotechnology
Cyclin‐dependent kinase 12 ( CDK 12) 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 CDK 12 in driving tumorigenesis. Here, we demonstrate that CDK 12 promotes tumor initiation as a novel regulator of cancer stem cells ( CSC s) and induces anti‐ HER 2 therapy resistance in human breast cancer. High CDK 12 expression caused by concurrent amplification of CDK 12 and HER 2 in breast cancer patients is associated with disease recurrence and poor survival. CDK 12 induces self‐renewal of breast CSC s and in vivo tumor‐initiating ability, and also reduces susceptibility to trastuzumab. Furthermore, CDK 12 kinase activity inhibition facilitates anticancer efficacy of trastuzumab in HER 2 + tumors, and mice bearing trastuzumab‐resistant HER 2 + tumor show sensitivity to an inhibitor of CDK 12. Mechanistically, the catalytic activity of CDK 12 is required for the expression of genes involved in the activation of ErbB‐ PI 3K‐ AKT or WNT ‐signaling cascades. These results suggest that CDK 12 is a major oncogenic driver and an actionable target for HER 2 + breast cancer to replace or augment current anti‐ HER 2 therapies.