title: IGF1/insulin receptor kinase inhibition by BMS-536924 is better tolerated than alloxan-induced hypoinsulinemia and more effective than metformin in the treatment of experimental insulin-responsive breast cancer.
abstract: Epidemiologic and experimental evidence suggest that a subset of breast cancer is insulin responsive, but it is unclear whether safe and effective therapies that target the insulin receptor (IR), which is homologous to oncogenes of the tyrosine kinase class, can be developed. We demonstrate that both pharmacologic inhibition of IR family tyrosine kinase activity and insulin deficiency have anti-neoplastic activity in a model of insulin-responsive breast cancer. Unexpectedly, in contrast to insulin deficiency, pharmacologic IR family inhibition does not lead to significant hyperglycemia and is well tolerated. We show that pharmacokinetic factors explain the tolerability of receptor inhibition relative to insulin deficiency, as the small molecule receptor kinase inhibitor BMS-536924 does not accumulate in muscle at levels sufficient to block insulin-stimulated glucose uptake. Metformin, which lowers insulin levels only in settings of hyperinsulinemia, had minimal activity in this normoinsulinemic model. These findings highlight the importance of tissue-specific drug accumulation as a determinant of efficacy and toxicity of tyrosine kinase inhibitors and suggest that therapeutic targeting of the IR family for cancer treatment is practical.
authors.affiliation: Department of Oncology, Lady Davis Research Institute of the Jewish General Hospital and Department of Oncology, McGill University, Montreal, Quebec, Canada.
authors.forename: Carly Jade
authors.initials: CJ
authors.lastname: Dool
authors.forename: Haider
authors.initials: H
authors.lastname: Mashhedi
authors.forename: Mahvash
authors.initials: M
authors.lastname: Zakikhani
authors.forename: Stéphanie
authors.initials: S
authors.lastname: David
authors.forename: Yunhua
authors.initials: Y
authors.lastname: Zhao
authors.forename: Elena
authors.initials: E
authors.lastname: Birman
authors.forename: Joan M
authors.initials: JM
authors.lastname: Carboni
authors.forename: Marco
authors.initials: M
authors.lastname: Gottardis
authors.forename: Marie-José
authors.initials: MJ
authors.lastname: Blouin
authors.forename: Michael
authors.initials: M
authors.lastname: Pollak
mesh_terms: D000496:Alloxan / Q000009:adverse effects*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D001562:Benzimidazoles / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors; D008687:Metformin / Q000009:adverse effects / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D011728:Pyridones / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; C504983:BMS 536924; D001562:Benzimidazoles; D007004:Hypoglycemic Agents; D007328:Insulin; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D007334:Insulin-Like Growth Factor I; D000496:Alloxan; D008687:Metformin; D017526:Receptor, IGF Type 1