Acquired resistance to everolimus in aromatase inhibitor-resistant breast cancer

Oncotarget
Mariko KimuraShin-Ichi Hayashi

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 sho...Continue Reading

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Citations

Jul 19, 2019·Cancer·Derek DustinSuzanne A W Fuqua
May 24, 2019·Breast Cancer : the Journal of the Japanese Breast Cancer Society·Kouki TsuboiShin-Ichi Hayashi
Aug 5, 2021·Breast Cancer : the Journal of the Japanese Breast Cancer Society·Yuna SuzukiShin-Ichi Hayashi
Aug 17, 2021·Breast Cancer Research : BCR·Jamie O BrettSeth A Wander

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Methods Mentioned

BETA
xenograft
fluorescence-activated cell sorter
flow cytometry
FCS
transfection
Assay
PCR

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