Targeting heat shock protein 90 with CUDC-305 overcomes erlotinib resistance in non-small cell lung cancer.

Abstract

CUDC-305 is a heat shock protein 90 (HSP90) inhibitor of the novel imidazopyridine class. Here, we report its activities in non-small cell lung cancer (NSCLC) cell lines with gene deregulations conferring primary or secondary resistance to epidermal growth factor receptor (EGFR) inhibitors. We show that CUDC-305 binds strongly to HSP90 extracted from erlotinib-resistant NSCLC cells (IC50 70 nmol/L). This result correlates well with the potent antiproliferative activity in erlotinib-resistant NSCLC cell lines (IC50 120-700 nmol/L) reported previously. Furthermore, it exhibits durable inhibition of multiple oncoproteins and induction of apoptosis in erlotinib-resistant NSCLC cells. CUDC-305 potently inhibits tumor growth in subcutaneous xenograft models of H1975 and A549, which harbor EGFR T790M mutation or K-ras mutations conferring acquired and primary erlotinib resistance, respectively. In addition, CUDC-305 significantly prolongs animal survival in orthotopic lung tumor models of H1975 and A549, which may be partially attributed to its preferential exposure in lung tissue. Furthermore, CUDC-305 is able to extend animal survival in a brain metastatic model of H1975, further confirming its ability to cross the blood-brain barrier. Correlating with its effects in various tumor models, CUDC-305 induces degradation of receptor tyrosine kinases and downstream signaling molecules of the PI3K/AKT and RAF/MEK/ERK pathways simultaneously, with concurrent induction of apoptosis in vivo. In a combination study, CUDC-305 enhanced the antitumor activity of a standard-of-care agent in the H1975 tumor model. These results suggest that CUDC-305 holds promise for the treatment of NSCLC with primary or acquired resistance to EGFR inhibitor therapy.

• Authors: Rudi Bao, Cheng-Jung Lai, Da-Gong Wang, Hui Qu, Ling Yin, Brian Zifcak, Xu Tao, Jing Wang, Ruzanna Atoyan, Maria Samson, Jeffrey Forrester, Guang-Xin Xu, Steven DellaRocca, Mylissa Borek, Hai-Xiao Zhai, Xiong Cai, Changgeng Qian
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 8 Issue 12 Pg. 3296-306 (Dec 2009) ISSN: 1538-8514 [Electronic] United States
• PMID: 19952121 (Publication Type: Journal Article)

Chemical References

• Benzodioxoles
• CUDC 305
• HSP90 Heat-Shock Proteins
• Imidazoles
• Protein Kinase Inhibitors
• Quinazolines
• Erlotinib Hydrochloride
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinases
• Paclitaxel

Topics

• Animals
• Apoptosis (drug effects)
• Benzodioxoles (metabolism, pharmacokinetics, pharmacology)
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm (drug effects)
• Drug Synergism
• Erlotinib Hydrochloride
• Female
• HSP90 Heat-Shock Proteins (antagonists & inhibitors, metabolism)
• Humans
• Imidazoles (metabolism, pharmacokinetics, pharmacology)
• Lung Neoplasms (drug therapy, metabolism, pathology)
• Mice
• Mice, Nude
• Mitogen-Activated Protein Kinases (metabolism)
• Paclitaxel (pharmacology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Quinazolines (pharmacology)
• Signal Transduction (drug effects)
• Survival Analysis
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays