Petrossian, KarinehKarinehPetrossianNguyen, DucDucNguyenCHIAO LOKanaya, NorikoNorikoKanayaSomlo, GeorgeGeorgeSomloCui, Yvonne XiaoyongYvonne XiaoyongCuiCHIUN-SHENG HUANGChen, ShiuanShiuanChen2020-03-232020-03-2320180167-6806https://www.scopus.com/inward/record.uri?eid=2-s2.0-85045030769&doi=10.1007%2fs10549-018-4779-x&partnerID=40&md5=5fb0619e154ce14568cc43b4f4a53149https://scholars.lib.ntu.edu.tw/handle/123456789/477702Purpose: HR+/HER2- aromatase inhibitor-resistant metastatic breast cancer can be treated with everolimus and a second AI until the cancer recurs. Targeting these everolimus-resistant patients with the latest standard of care, CDK4/6 inhibitors, has not been clearly addressed. Understanding the signaling transduction pathways, which everolimus resistance activates, will elucidate the mechanisms and offer treatment strategies of everolimus resistance. Methods: To mimic the clinical setting, letrozole-resistant cells were used to generate an everolimus-resistant model (RAD-R). Reverse phase protein array (RPPA) was performed to reveal changes in the signaling transduction pathways, and expression levels of key proteins were analyzed. Inhibitors targeting the major signaling pathways, a CDK4/6 inhibitor palbociclib and a mTORC1/2 inhibitor (MLN0128), were evaluated to establish resistance mechanisms of RAD-R. Results: RPPA results from RAD-R indicated changes to significant regulatory pathways and upregulation of p-AKT expression level associating with everolimus resistance. MLN0128, that inhibits the AKT phosphorylation, effectively suppressed the proliferation of RAD-R cells while treatment with palbociclib had no effect. Conclusion: Among the many signaling transduction pathways, which are altered post everolimus resistance, targeting dual mTORC1/2 is a possible option for patients who have recurrent disease from previous everolimus treatment.enAI resistanceEverolimusMLN0128MTOR inhibitors[SDGs]SDG3everolimus; palbociclib; protein kinase B; sapanisertib; benzoxazole derivative; biological marker; estrogen receptor; everolimus; protein kinase B; protein kinase inhibitor; pyrimidine derivative; sapanisertib; target of rapamycin kinase; Article; breast cancer cell line; cancer inhibition; cell proliferation; controlled study; drug resistance; enzyme phosphorylation; priority journal; protein expression level; signal transduction; upregulation; antagonists and inhibitors; breast tumor; drug effect; female; human; IC50; metabolism; phosphorylation; tumor cell line; Benzoxazoles; Biomarkers; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Everolimus; Female; Humans; Inhibitory Concentration 50; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrimidines; Receptors, Estrogen; Signal Transduction; TOR Serine-Threonine Kinasesjournal article10.1007/s10549-018-4779-x296235772-s2.0-85045030769