Acquired resistance to everolimus in aromatase inhibitor-resistant breast cancer

Abstract

// Mariko Kimura 1, 2, 5 , Toru Hanamura 1, 3 , Kouki Tsuboi 1 , Yosuke Kaneko 1 , Yuri Yamaguchi 4 , Toshifumi Niwa 1 , Kazutaka Narui 5 , Itaru Endo 2 and Shin-Ichi Hayashi 1 1 Department of Molecular and Functional Dynamics, Tohoku University Graduate School of Medicine, Sendai, Japan 2 Department of Gastroenterological Surgery and Clinical Oncology, Yokohama City University Graduate School of Medicine, Yokohama, Japan 3 Division of Breast and Endocrine Surgery, Department of Surgery, Shinshu University School of Medicine, Nagano, Japan 4 Research Institute for Clinical Oncology, Saitama Cancer Center, Ina-machi, Japan 5 Department of Breast and Thyroid Surgery, Yokohama City University Medical Center, Yokohama, Japan Correspondence to: Mariko Kimura, email: mar016@outlook.jp Keywords: breast cancer; estrogen receptor; endocrine resistance; mTOR inhibitor; everolimus Received: November 16, 2017     Accepted: March 23, 2018     Published: April 20, 2018 ABSTRACT 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.