Simultaneous CK2/TNIK/DYRK1 inhibition by 108600 suppresses triple negative breast cancer stem cells and chemotherapy-resistant disease.
Katsutoshi SatoAmol A PadgaonkarStacey J BakerStephen C CosenzaOlga RechkoblitD R C Venkata SubbaiahJosep Domingo-DomenechAlison BartkowskiElisa R PortAneel K AggarwalM V Ramana ReddyHanna Y IrieE Premkumar ReddyPublished in: Nature communications (2021)
Triple negative breast cancer (TNBC) remains challenging because of heterogeneous responses to chemotherapy. Incomplete response is associated with a greater risk of metastatic progression. Therefore, treatments that target chemotherapy-resistant TNBC and enhance chemosensitivity would improve outcomes for these high-risk patients. Breast cancer stem cell-like cells (BCSCs) have been proposed to represent a chemotherapy-resistant subpopulation responsible for tumor initiation, progression and metastases. Targeting this population could lead to improved TNBC disease control. Here, we describe a novel multi-kinase inhibitor, 108600, that targets the TNBC BCSC population. 108600 treatment suppresses growth, colony and mammosphere forming capacity of BCSCs and induces G2M arrest and apoptosis of TNBC cells. In vivo, 108600 treatment of mice bearing triple negative tumors results in the induction of apoptosis and overcomes chemotherapy resistance. Finally, treatment with 108600 and chemotherapy suppresses growth of pre-established TNBC metastases, providing additional support for the clinical translation of this agent to clinical trials.
Keyphrases
- cancer stem cells
- locally advanced
- clinical trial
- cell cycle arrest
- signaling pathway
- oxidative stress
- squamous cell carcinoma
- endoplasmic reticulum stress
- induced apoptosis
- cell death
- small cell lung cancer
- newly diagnosed
- ejection fraction
- type diabetes
- randomized controlled trial
- combination therapy
- replacement therapy
- cell cycle
- open label
- phase iii