Karineh Petrossian1, Duc Nguyen1, Chiao Lo2, Noriko Kanaya1, George Somlo3, Yvonne Xiaoyong Cui1, Chiun-Sheng Huang2, Shiuan Chen4. 1. Department of Cancer Biology, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Kaplan CRB, Room 2002C, Duarte, CA, USA. 2. Department of Breast Health, National Taiwan University Hospital, Taipei City, Taiwan. 3. Department of Medical Oncology and Therapeutics Research, City of Hope Medical Center, Duarte, CA, 91010, USA. 4. Department of Cancer Biology, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Kaplan CRB, Room 2002C, Duarte, CA, USA. schen@coh.org.
Abstract
PURPOSE: 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.
PURPOSE: 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.
Entities:
Keywords:
AI resistance; Everolimus; MLN0128; MTOR inhibitors
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