title: Activation of IGF1R/p110β/AKT/mTOR confers resistance to α-specific PI3K inhibition.
abstract: BACKGROUND
  The PI3K pathway is hyperactivated in many cancers, including 70 % of breast cancers. Pan- and isoform-specific inhibitors of the PI3K pathway are currently being evaluated in clinical trials. However, the clinical responses to PI3K inhibitors when used as single agents are not as efficient as expected.
  
  
  METHODS
  In order to anticipate potential molecular mechanisms of resistance to the p110α isoform-selective inhibitor BYL719, we developed resistant breast cancer cell lines, assessed the concomitant changes in cellular signaling pathways using unbiased phosphotyrosine proteomics and characterized the mechanism of resistance using pharmacological inhibitors.
  
  
  RESULTS
  We found an increase in IGF1R, IRS1/IRS2 and p85 phosphorylation in the resistant lines. Co-immunoprecipitation experiments identified an IGF1R/IRS/p85/p110β complex that causes the activation of AKT/mTOR/S6K and stifles the effects of BYL719. Pharmacological inhibition of members of this complex reduced mTOR/S6K activation and restored sensitivity to BYL719.
  
  
  CONCLUSIONS
  Our study demonstrates that the IGF1R/p110β/AKT/mTOR axis confers resistance to BYL719 in PIK3CA mutant breast cancers. This provides a rationale for the combined targeting of p110α with IGF1R or p110β in patients with breast tumors harboring PIK3CA mutations.
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Maulbeerstraße 66, 4058, Basel, Switzerland.|Novartis Institutes for Biomedical Research, Postfach, CH-4002, Basel, Switzerland.
authors.forename: Cedric
authors.initials: C
authors.lastname: Leroy
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Maulbeerstraße 66, 4058, Basel, Switzerland.|Novartis Institutes for Biomedical Research, Postfach, CH-4002, Basel, Switzerland.
authors.forename: Pedro
authors.initials: P
authors.lastname: Ramos
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Maulbeerstraße 66, 4058, Basel, Switzerland.
authors.forename: Karen
authors.initials: K
authors.lastname: Cornille
authors.affiliation: Novartis Institutes for Biomedical Research, Postfach, CH-4002, Basel, Switzerland.
authors.forename: Debora
authors.initials: D
authors.lastname: Bonenfant
authors.affiliation: Novartis Institutes for Biomedical Research, Postfach, CH-4002, Basel, Switzerland.
authors.forename: Christine
authors.initials: C
authors.lastname: Fritsch
authors.affiliation: Novartis Institutes for Biomedical Research, Postfach, CH-4002, Basel, Switzerland.
authors.forename: Hans
authors.initials: H
authors.lastname: Voshol
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Maulbeerstraße 66, 4058, Basel, Switzerland. bentires@fmi.ch.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Bentires-Alj
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005260:Female; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D013844:Thiazoles / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D058543:Class Ia Phosphatidylinositol 3-Kinase; D055504:Insulin Receptor Substrate Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin; D058570:TOR Serine-Threonine Kinases; D013844:Thiazoles; C000597236:IGF1R protein, human; C526292:IRS1 protein, human; C526297:IRS2 protein, human; C585539:Alpelisib; C546842:MTOR protein, human; C484760:PIK3CA protein, human
keywords: Breast cancer; Phosphatidylinositol 3-kinase; Resistance; p110α; p110β