TY - JOUR
T1 - Identification of Kinase Targets for Enhancing the Antitumor Activity of Eribulin in Triple-Negative Breast Cell Lines
AU - Xie, Xuemei
AU - Lee, Jangsoon
AU - Fuson, Jon A.
AU - Liu, Huey
AU - Iwase, Toshiaki
AU - Yun, Kyuson
AU - Margain, Cori
AU - Tripathy, Debu
AU - Ueno, Naoto T.
N1 - Funding Information:
This research was funded by the Morgan Welch Inflammatory Breast Cancer Research Program, the State of Texas Rare and Aggressive Breast Cancer Research Program, the NIH/NCI grant P30CA016672 (using the Cytogenetics and Cell Authentication Core and the Research Animal Support Facility), and Eisai Co., Ltd.
Funding Information:
We thank Ashli Nguyen-Villarreal and Sarah Bronson of the Department of Scientific Publications at The University of Texas MD Anderson Cancer Center for their expert editorial assistance. We acknowledge Daohong Zhou and Daifeng Jiang for their assistance with the high-throughput kinome library RNAi screening, which was performed at the Target Identification Facility of the Greehey Children’s Cancer Research Institute at University of Texas Health San Antonio and the Drug Discovery and Structural Biology Shared Resources of the Mays Cancer Center at University of Texas Health San Antonio. The facilities were partially supported by P30CA054174 from NIH and RP160844 from CPRIT.
Publisher Copyright:
© 2023 by the authors.
PY - 2023/2/28
Y1 - 2023/2/28
N2 - 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.
AB - 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.
KW - copanlisib
KW - eribulin
KW - everolimus
KW - the PI3K/mTOR pathway
KW - triple-negative breast cancer
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U2 - 10.3390/biomedicines11030735
DO - 10.3390/biomedicines11030735
M3 - Article
C2 - 36979714
AN - SCOPUS:85151970570
SN - 2227-9059
VL - 11
JO - Biomedicines
JF - Biomedicines
IS - 3
M1 - 735
ER -