Acquired resistance to everolimus in aromatase inhibitor-resistant breast cancer
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Mariko Kimura1,2,5, Toru Hanamura1,3, Kouki Tsuboi1, Yosuke Kaneko1, Yuri Yamaguchi4, Toshifumi Niwa1, Kazutaka Narui5, Itaru Endo2 and Shin-Ichi Hayashi1
1Department of Molecular and Functional Dynamics, Tohoku University Graduate School of Medicine, Sendai, Japan
2Department of Gastroenterological Surgery and Clinical Oncology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
3Division of Breast and Endocrine Surgery, Department of Surgery, Shinshu University School of Medicine, Nagano, Japan
4Research Institute for Clinical Oncology, Saitama Cancer Center, Ina-machi, Japan
5Department of Breast and Thyroid Surgery, Yokohama City University Medical Center, Yokohama, Japan
Mariko Kimura, email: email@example.com
Keywords: breast cancer; estrogen receptor; endocrine resistance; mTOR inhibitor; everolimus
Received: November 16, 2017 Accepted: March 23, 2018 Published: April 20, 2018
We previously reported the establishment of several types of long-term estrogen-depleted-resistant (EDR) cell lines from MCF-7 breast cancer cells. Type 1 EDR cells exhibited the best-studied mechanism of aromatase inhibitor (AI) resistance, in which estrogen receptor (ER) expression remained positive and PI3K signaling was upregulated. Type 2 EDR cells showed reduced ER activity and upregulated JNK-related signaling. The mTOR inhibitor everolimus reduced growth in cells similar to Type 1 EDR cells. The present study generated everolimus-resistant (EvR) cells from Types 1 and 2 EDR cells following long-term exposure to everolimus in vitro. These EvR cells modeled resistance to AI and everolimus combination therapies following first-line AI treatment failure. In Type 1 EvR cells, everolimus resistance was dependent on MAPK signaling; single agents were not effective, but hormonal therapy combined with a kinase inhibitor effectively reduced cell growth. In Type 2 EvR cells, ER expression remained negative and a JNK inhibitor was ineffective, but a Src inhibitor reduced cell growth. The mechanism of acquired everolimus resistance appears to vary depending on the mechanism of AI resistance. Strategies targeting resistant tumors should be tailored based on the resistance mechanisms, as these mechanisms impact therapeutic efficacy.
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