title: Dual mTORC1/2 and HER2 blockade results in antitumor activity in preclinical models of breast cancer resistant to anti-HER2 therapy.
abstract: OBJECTIVE
  The PI3K/Akt/mTOR pathway is an attractive target in HER2-positive breast cancer that is refractory to anti-HER2 therapy. The hypothesis is that the suppression of this pathway results in sensitization to anti-HER2 agents. However, this combinatorial strategy has not been comprehensively tested in models of trastuzumab and lapatinib resistance.
  
  
  METHODS
  We analyzed in vitro cell viability and induction of apoptosis in five different cell lines resistant to trastuzumab and lapatinib. Inhibition of HER2/HER3 phosphorylation, PI3K/Akt/mTOR, and extracellular signal-regulated kinase (ERK) signaling pathways was evaluated by Western blotting. Tumor growth inhibition after treatment with lapatinib, INK-128, or the combination of both agents was evaluated in three different animal models: two cell-based xenograft models refractory to both trastuzumab and lapatinib and a xenograft derived from a patient who relapsed on trastuzumab-based therapy.
  
  
  RESULTS
  The addition of lapatinib to INK-128 prevented both HER2 and HER3 phosphorylation induced by INK-128, resulting in inhibition of both PI3K/Akt/mTOR and ERK pathways. This dual blockade produced synergistic induction of cell death in five different HER2-positive cell lines resistant to trastuzumab and lapatinib. In vivo, both cell line-based and patient-derived xenografts showed exquisite sensitivity to the antitumor activity of the combination of lapatinib and INK-128, which resulted in durable tumor shrinkage and exhibited no signs of toxicity in these models.
  
  
  CONCLUSIONS
  The simultaneous blockade of both PI3K/Akt/mTOR and ERK pathways obtained by combining lapatinib with INK-128 acts synergistically in inducing cell death and tumor regression in breast cancer models refractory to anti-HER2 therapy.
authors.affiliation: Department of Experimental Therapeutics Laboratory, Vall d'Hebron Institute of Oncology, Pg Vall d'Hebron, Barcelona, Spain.
authors.forename: Celina
authors.initials: C
authors.lastname: García-García
authors.forename: Yasir H
authors.initials: YH
authors.lastname: Ibrahim
authors.forename: Violeta
authors.initials: V
authors.lastname: Serra
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Calvo
authors.forename: Marta
authors.initials: M
authors.lastname: Guzmán
authors.forename: Judit
authors.initials: J
authors.lastname: Grueso
authors.forename: Claudia
authors.initials: C
authors.lastname: Aura
authors.forename: José
authors.initials: J
authors.lastname: Pérez
authors.forename: Katti
authors.initials: K
authors.lastname: Jessen
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Christian
authors.initials: C
authors.lastname: Rommel
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.forename: Maurizio
authors.initials: M
authors.lastname: Scaltriti
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001583:Benzoxazoles / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D000077341:Lapatinib; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008819:Mice, Nude; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000225:Adenine / Q000031:analogs & derivatives
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001583:Benzoxazoles; D048049:Extracellular Signal-Regulated MAP Kinases; D000077341:Lapatinib; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; D000068878:Trastuzumab; C493245:CRTC2 protein, human; C546842:MTOR protein, human; C572449:sapanisertib; D000225:Adenine