Identification of Kinase Targets for Enhancing the Antitumor Activity of Eribulin in Triple-Negative Breast Cell Lines
Xuemei Xie,
Jangsoon Lee,
Jon A. Fuson,
Huey Liu,
Toshiaki Iwase,
Kyuson Yun,
Cori Margain,
Debu Tripathy,
Naoto T. Ueno
Affiliations
Xuemei Xie
Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Jangsoon Lee
Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Jon A. Fuson
Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Huey Liu
Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Toshiaki Iwase
Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Kyuson Yun
Research Institute at Houston Methodist, Weill Cornell Medical College, Houston, TX 77030, USA
Cori Margain
Empiri Inc., Houston, TX 77054, USA
Debu Tripathy
Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Naoto T. Ueno
Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Background: Triple-negative breast cancer (TNBC) is the most aggressive molecular subtype of breast cancer, and current treatments are only partially effective in disease control. More effective combination approaches are needed to improve the survival of TNBC patients. Eribulin mesylate, a non-taxane microtubule dynamics inhibitor, is approved by the U.S. Food and Drug Administration to treat metastatic breast cancer after at least two previous chemotherapeutic regimens. However, eribulin as a single agent has limited therapeutic efficacy against TNBC. Methods: High-throughput kinome library RNAi screening, Ingenuity Pathway Analysis, and STRING analysis were performed to identify target kinases for combination with eribulin. The identified combinations were validated using in vivo and ex vivo proliferation assays. Results: We identified 135 potential kinase targets whose inhibition enhanced the antiproliferation effect of eribulin in TNBC cells, with the PI3K/Akt/mTOR and the MAPK/JNK pathways emerging as the top candidates. Indeed, copanlisib (pan-class I PI3K inhibitor), everolimus (mTOR inhibitor), trametinib (MEK inhibitor), and JNK-IN-8 (pan-JNK inhibitor) produced strong synergistic antiproliferative effects when combined with eribulin, and the PI3K and mTOR inhibitors had the most potent effects in vitro. Conclusions: Our data suggest a new strategy of combining eribulin with PI3K or mTOR inhibitors to treat TNBC.
