The HSP90 Inhibitor NVP-AUY922 Potently Inhibits Non–Small Cell Lung Cancer Growth

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  • Edward B. Garon
    Authors' Affiliations: 1Department of Medicine, Division of Hematology/Oncology, 2Department of Medicine, Division of Pulmonary Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California; 3Novartis Oncology Translational Medicine, Florham Park, New Jersey; 4Novartis Institutes for BioMedical Research; 5Novartis Pharma AG, Basel, Switzerland; and 6Division of Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts
  • Richard S. Finn
    Authors' Affiliations: 1Department of Medicine, Division of Hematology/Oncology, 2Department of Medicine, Division of Pulmonary Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California; 3Novartis Oncology Translational Medicine, Florham Park, New Jersey; 4Novartis Institutes for BioMedical Research; 5Novartis Pharma AG, Basel, Switzerland; and 6Division of Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts
  • Habib Hamidi
    Authors' Affiliations: 1Department of Medicine, Division of Hematology/Oncology, 2Department of Medicine, Division of Pulmonary Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California; 3Novartis Oncology Translational Medicine, Florham Park, New Jersey; 4Novartis Institutes for BioMedical Research; 5Novartis Pharma AG, Basel, Switzerland; and 6Division of Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts
  • Judy Dering
    Authors' Affiliations: 1Department of Medicine, Division of Hematology/Oncology, 2Department of Medicine, Division of Pulmonary Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California; 3Novartis Oncology Translational Medicine, Florham Park, New Jersey; 4Novartis Institutes for BioMedical Research; 5Novartis Pharma AG, Basel, Switzerland; and 6Division of Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts
  • Sharon Pitts
    Authors' Affiliations: 1Department of Medicine, Division of Hematology/Oncology, 2Department of Medicine, Division of Pulmonary Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California; 3Novartis Oncology Translational Medicine, Florham Park, New Jersey; 4Novartis Institutes for BioMedical Research; 5Novartis Pharma AG, Basel, Switzerland; and 6Division of Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts
  • Naeimeh Kamranpour
    Authors' Affiliations: 1Department of Medicine, Division of Hematology/Oncology, 2Department of Medicine, Division of Pulmonary Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California; 3Novartis Oncology Translational Medicine, Florham Park, New Jersey; 4Novartis Institutes for BioMedical Research; 5Novartis Pharma AG, Basel, Switzerland; and 6Division of Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts
  • Amrita J. Desai
    Authors' Affiliations: 1Department of Medicine, Division of Hematology/Oncology, 2Department of Medicine, Division of Pulmonary Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California; 3Novartis Oncology Translational Medicine, Florham Park, New Jersey; 4Novartis Institutes for BioMedical Research; 5Novartis Pharma AG, Basel, Switzerland; and 6Division of Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts
  • Wylie Hosmer
    Authors' Affiliations: 1Department of Medicine, Division of Hematology/Oncology, 2Department of Medicine, Division of Pulmonary Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California; 3Novartis Oncology Translational Medicine, Florham Park, New Jersey; 4Novartis Institutes for BioMedical Research; 5Novartis Pharma AG, Basel, Switzerland; and 6Division of Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts
  • Susan Ide
    Authors' Affiliations: 1Department of Medicine, Division of Hematology/Oncology, 2Department of Medicine, Division of Pulmonary Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California; 3Novartis Oncology Translational Medicine, Florham Park, New Jersey; 4Novartis Institutes for BioMedical Research; 5Novartis Pharma AG, Basel, Switzerland; and 6Division of Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts
  • Emin Avsar
    Authors' Affiliations: 1Department of Medicine, Division of Hematology/Oncology, 2Department of Medicine, Division of Pulmonary Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California; 3Novartis Oncology Translational Medicine, Florham Park, New Jersey; 4Novartis Institutes for BioMedical Research; 5Novartis Pharma AG, Basel, Switzerland; and 6Division of Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts
  • Michael Rugaard Jensen
    Authors' Affiliations: 1Department of Medicine, Division of Hematology/Oncology, 2Department of Medicine, Division of Pulmonary Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California; 3Novartis Oncology Translational Medicine, Florham Park, New Jersey; 4Novartis Institutes for BioMedical Research; 5Novartis Pharma AG, Basel, Switzerland; and 6Division of Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts
  • Cornelia Quadt
    Authors' Affiliations: 1Department of Medicine, Division of Hematology/Oncology, 2Department of Medicine, Division of Pulmonary Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California; 3Novartis Oncology Translational Medicine, Florham Park, New Jersey; 4Novartis Institutes for BioMedical Research; 5Novartis Pharma AG, Basel, Switzerland; and 6Division of Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts
  • Manway Liu
    Authors' Affiliations: 1Department of Medicine, Division of Hematology/Oncology, 2Department of Medicine, Division of Pulmonary Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California; 3Novartis Oncology Translational Medicine, Florham Park, New Jersey; 4Novartis Institutes for BioMedical Research; 5Novartis Pharma AG, Basel, Switzerland; and 6Division of Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts
  • Steven M. Dubinett
    Authors' Affiliations: 1Department of Medicine, Division of Hematology/Oncology, 2Department of Medicine, Division of Pulmonary Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California; 3Novartis Oncology Translational Medicine, Florham Park, New Jersey; 4Novartis Institutes for BioMedical Research; 5Novartis Pharma AG, Basel, Switzerland; and 6Division of Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts
  • Dennis J. Slamon
    Authors' Affiliations: 1Department of Medicine, Division of Hematology/Oncology, 2Department of Medicine, Division of Pulmonary Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California; 3Novartis Oncology Translational Medicine, Florham Park, New Jersey; 4Novartis Institutes for BioMedical Research; 5Novartis Pharma AG, Basel, Switzerland; and 6Division of Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts

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<jats:title>Abstract</jats:title><jats:p>Heat shock protein 90 (HSP90) is involved in protein folding and functions as a chaperone for numerous client proteins, many of which are important in non–small cell lung cancer (NSCLC) pathogenesis. We sought to define preclinical effects of the HSP90 inhibitor NVP-AUY922 and identify predictors of response. We assessed in vitro effects of NVP-AUY922 on proliferation and protein expression in NSCLC cell lines. We evaluated gene expression changes induced by NVP-AUY922 exposure. Xenograft models were evaluated for tumor control and biological effects. NVP-AUY922 potently inhibited in vitro growth in all 41 NSCLC cell lines evaluated with IC50 &lt; 100 nmol/L. IC100 (complete inhibition of proliferation) &lt; 40 nmol/L was seen in 36 of 41 lines. Consistent gene expression changes after NVP-AUY922 exposure involved a wide range of cellular functions, including consistently decreased dihydrofolate reductase after exposure. NVP-AUY922 slowed growth of A549 (KRAS-mutant) xenografts and achieved tumor stability and decreased EGF receptor (EGFR) protein expression in H1975 xenografts, a model harboring a sensitizing and a resistance mutation for EGFR-tyrosine kinase inhibitors in the EGFR gene. These data will help inform the evaluation of correlative data from a recently completed phase II NSCLC trial and a planned phase IB trial of NVP-AUY922 in combination with pemetrexed in NSCLCs. Mol Cancer Ther; 12(6); 890–900. ©2013 AACR.</jats:p>

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