title: PI3K independent activation of mTORC1 as a target in lapatinib-resistant ERBB2+ breast cancer cells.
abstract: Therapies targeting the ERBB2 receptor, including the kinase inhibitor lapatinib (Tykerb, GlaxoSmithKline), have improved clinical outcome for women with ERBB2-amplified breast cancer. However, acquired resistance to lapatinib remains a significant clinical problem, and the mechanisms governing resistance remain poorly understood. We sought to define molecular alterations that confer an acquired lapatinib resistance phenotype in ER-/ERBB2+ human breast cancer cells. ERBB2-amplified SKBR3 breast cancer cells were rendered resistant to lapatinib via culture in increasing concentrations of the drug, and molecular changes associated with a resistant phenotype were interrogated using a collaborative enzyme-enhanced immunoassay platform and immunoblotting techniques for detection of phosphorylated signaling cascade proteins. Interestingly, despite apparent inactivation of the PI3K/AKT signaling pathway, resistant cells exhibited constitutive activation of mammalian target of rapamycin complex 1 (mTORC1) and were highly sensitive to mTOR inhibition with rapamycin and the dual PI3K/mTOR inhibitor NVP-BEZ235. These data demonstrate a role for downstream activation of mTORC1 in the absence of molecular alterations leading to PI3K/AKT hyperactivation as a potential mechanism of lapatinib resistance in this model of ERBB2+ breast cancer and support the rationale of combination or sequential therapy using ERBB2 and mTOR-targeting molecules to prevent or target resistance to lapatinib. Moreover, our data suggest that assessment of mTOR substrate phosphorylation (i.e., S6) may serve as a more robust biomarker to predict sensitivity to mTOR inhibitors in the context of lapatinib resistance than PI3K mutations, loss of PTEN and p-AKT levels.
authors.affiliation: Division of Hematology and Oncology, University of Miami Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA.
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Jegg
authors.forename: Toby M
authors.initials: TM
authors.lastname: Ward
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Iorns
authors.forename: Nicholas
authors.initials: N
authors.lastname: Hoe
authors.forename: Jinyao
authors.initials: J
authors.lastname: Zhou
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Liu
authors.forename: Sharat
authors.initials: S
authors.lastname: Singh
authors.forename: Ralf
authors.initials: R
authors.lastname: Landgraf
authors.forename: Mark D
authors.initials: MD
authors.lastname: Pegram
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D000077341:Lapatinib; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D009154:Mutation; D051058:Oncogene Protein v-akt / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011506:Proteins / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases
chemical_list: D000077341:Lapatinib; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D011506:Proteins; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; C508053:ERBB2 protein, human; C494929:PTEN protein, human