Acquired resistance to everolimus in aromatase inhibitor-resistant breast cancer.

Acquired resistance to everolimus in aromatase inhibitor-resistant breast cancer. Oncotarget. 2018 Apr 20;9(30):21468-21477 Authors: Kimura M, Hanamura T, Tsuboi K, Kaneko Y, Yamaguchi Y, Niwa T, Narui K, Endo I, Hayashi SI 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 targeti...
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research