Breast cancer research : BCR · 2014
Overcoming endocrine resistance due to reduced PTEN levels in estrogen receptor-positive breast cancer by co-targeting mammalian target of rapamycin, protein kinase B, or mitogen-activated protein kinase kinase.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Fu Xiaoyong, Creighton Chad J, Biswal Nrusingh C, Kumar Vijetha, Shea Martin, Herrera Sabrina, Contreras Alejandro, Gutierrez Carolina, Wang Tao, Nanda Sarmistha, Giuliano Mario, Morrison Gladys, Nardone Agostina, Karlin Kristen L, Westbrook Thomas F, Heiser Laura M, Anur Pavana, Spellman Paul, Guichard Sylvie M, Smith Paul D, Davies Barry R, Klinowska Teresa, Lee Adrian V, Mills Gordon B, Rimawi Mothaffar F, Hilsenbeck Susan G, Gray Joe W, Joshi Amit, Osborne C Kent, Schiff Rachel
Аннотация
INTRODUCTION: Activation of the phosphatidylinositol 3-kinase (PI3K) pathway in estrogen receptor α (ER)-positive breast cancer is associated with reduced ER expression and activity, luminal B subtype, and poor outcome. Phosphatase and tensin homolog (PTEN), a negative regulator of this pathway, is typically lost in ER-negative breast cancer. We set out to clarify the role of reduced PTEN levels in endocrine resistance, and to explore the combination of newly developed PI3K downstream kinase inhibitors to overcome this resistance.
METHODS: Altered cellular signaling, gene expression, and endocrine sensitivity were determined in inducible PTEN-knockdown ER-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer cell and/or xenograft models. Single or two-agent combinations of kinase inhibitors were examined to improve endocrine therapy.
RESULTS: Moderate PTEN reduction was sufficient to enhance PI3K signaling, generate a gene signature associated with the luminal B subtype of breast cancer, and cause endocrine resistance in vitro and in vivo. The mammalian target of rapamycin (mTOR), protein kinase B (AKT), or mitogen-activated protein kinase kinase (MEK) inhibitors, alone or in combination, improved endocrine therapy, but the efficacy varied by PTEN levels, type of endocrine therapy, and the specific inhibitor(s). A single-agent AKT inhibitor combined with fulvestrant conferred superior efficacy in overcoming resistance, inducing apoptosis and tumor regression.
CONCLUSIONS: Moderate reduction in PTEN, without complete loss, can activate the PI3K pathway to cause endocrine resistance in ER-positive breast cancer, which can be overcome by combining endocrine therapy with inhibitors of the PI3K pathway. Our data suggests that the ER degrader fulvestrant, to block both ligand-dependent and -independent ER signaling, combined with an AKT inhibitor is an effective strategy to test in patients.
METHODS: Altered cellular signaling, gene expression, and endocrine sensitivity were determined in inducible PTEN-knockdown ER-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer cell and/or xenograft models. Single or two-agent combinations of kinase inhibitors were examined to improve endocrine therapy.
RESULTS: Moderate PTEN reduction was sufficient to enhance PI3K signaling, generate a gene signature associated with the luminal B subtype of breast cancer, and cause endocrine resistance in vitro and in vivo. The mammalian target of rapamycin (mTOR), protein kinase B (AKT), or mitogen-activated protein kinase kinase (MEK) inhibitors, alone or in combination, improved endocrine therapy, but the efficacy varied by PTEN levels, type of endocrine therapy, and the specific inhibitor(s). A single-agent AKT inhibitor combined with fulvestrant conferred superior efficacy in overcoming resistance, inducing apoptosis and tumor regression.
CONCLUSIONS: Moderate reduction in PTEN, without complete loss, can activate the PI3K pathway to cause endocrine resistance in ER-positive breast cancer, which can be overcome by combining endocrine therapy with inhibitors of the PI3K pathway. Our data suggests that the ER degrader fulvestrant, to block both ligand-dependent and -independent ER signaling, combined with an AKT inhibitor is an effective strategy to test in patients.
Предметные рубрики MeSH
AnimalsAntineoplastic Agents, HormonalBreast NeoplasmsDoxycyclineDrug Resistance, NeoplasmEstradiolFemaleFulvestrantGene ExpressionGene Knockdown TechniquesHumansMCF-7 CellsMice, NudeMitogen-Activated Protein KinasesMolecular Targeted TherapyNeoplasms, Hormone-DependentPTEN PhosphohydrolasePhosphatidylinositol 3-KinasesProtein Kinase InhibitorsProto-Oncogene Proteins c-aktReceptors, EstrogenSignal TransductionSirolimusTOR Serine-Threonine KinasesTamoxifenXenograft Model Antitumor Assays