The HSP90 inhibitor ganetespib potentiates the antitumor activity of EGFR tyrosine kinase inhibition in mutant and wild-type non-small cell lung cancer.

Abstract

Small molecule inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase activity, such as erlotinib and gefitinib, revolutionized therapy for non-small cell lung cancer (NSCLC) patients whose tumors harbor activating EGFR mutations. However, mechanisms to overcome the invariable development of acquired resistance to such agents, as well as realizing their full clinical potential within the context of wild-type EGFR (WT-EGFR) disease, remain to be established. Here, the antitumor efficacy of targeted EGFR tyrosine kinase inhibitors (TKIs) and the HSP90 inhibitor ganetespib, alone and in combination, were evaluated in NSCLC. Ganetespib potentiated the efficacy of erlotinib in TKI-sensitive, mutant EGFR-driven NCI-HCC827 xenograft tumors, with combination treatment causing significant tumor regressions. In erlotinib-resistant NCI-H1975 xenografts, concurrent administration of ganetespib overcame erlotinib resistance to significantly improve tumor growth inhibition. Ganetespib co-treatment also significantly enhanced antitumor responses to afatinib in the same model. In WT-EGFR cell lines, ganetespib potently reduced cell viability. In NCI-H1666 cells, ganetespib-induced loss of client protein expression, perturbation of oncogenic signaling pathways, and induction of apoptosis translated to robust single-agent activity in vivo. Dual ganetespib/erlotinib therapy induced regressions in NCI-H322 xenograft tumors, indicating that the sensitizing properties of ganetespib for erlotinib were conserved within the WT-EGFR setting. Mechanistically, combined ganetespib/erlotinib exposure stabilized EGFR protein levels in an inactive state and completely abrogated extracellular-signal-regulated kinase (ERK) and AKT signaling activity. Thus, selective HSP90 blockade by ganetespib represents a potentially important complementary strategy to targeted TKI inhibition alone for inducing substantial antitumor responses and overcoming resistance, in both the mutant and WT-EGFR settings.

• Authors: Donald L Smith, Jaime Acquaviva, Manuel Sequeira, John-Paul Jimenez, Chaohua Zhang, Jim Sang, Richard C Bates, David A Proia
• Journal: Targeted oncology (Target Oncol) Vol. 10 Issue 2 Pg. 235-45 (Jun 2015) ISSN: 1776-260X [Electronic] France
• PMID: 25077897 (Publication Type: Comparative Study, Journal Article)

Chemical References

• HSP90 Heat-Shock Proteins
• Protein Kinase Inhibitors
• STA 9090
• Triazoles
• EGFR protein, human
• ErbB Receptors

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm
• Drug Synergism
• ErbB Receptors (antagonists & inhibitors, genetics, metabolism)
• Female
• HSP90 Heat-Shock Proteins (antagonists & inhibitors, metabolism)
• Humans
• Lung Neoplasms (drug therapy, genetics, metabolism, pathology)
• Mice, SCID
• Mutation
• Protein Kinase Inhibitors (pharmacology)
• Signal Transduction (drug effects)
• Time Factors
• Triazoles (pharmacology)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays