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

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...

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Published in:Molecular cancer therapeutics 2009-12, Vol.8 (12), p.3296-3306
Main Authors: Bao, Rudi, Lai, Cheng-Jung, Wang, Da-Gong, Qu, Hui, Yin, Ling, Zifcak, Brian, Tao, Xu, Wang, Jing, Atoyan, Ruzanna, Samson, Maria, Forrester, Jeffrey, Xu, Guang-Xin, DellaRocca, Steven, Borek, Mylissa, Zhai, Hai-Xiao, Cai, Xiong, Qian, Changgeng
Format: Article
Language:English
Subjects:
Animals
Apoptosis - drug effects
Benzodioxoles - metabolism
Benzodioxoles - pharmacokinetics
Benzodioxoles - pharmacology
Carcinoma, Non-Small-Cell Lung - drug therapy
Carcinoma, Non-Small-Cell Lung - metabolism
Carcinoma, Non-Small-Cell Lung - pathology
Cell Line, Tumor
Cell Proliferation - drug effects
CUDC-305
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm - drug effects
Drug Synergism
Erlotinib Hydrochloride
erlotinib resistance
Female
HSP90 Heat-Shock Proteins - antagonists & inhibitors
HSP90 Heat-Shock Proteins - metabolism
Humans
Imidazoles - metabolism
Imidazoles - pharmacokinetics
Imidazoles - pharmacology
Lung Neoplasms - drug therapy
Lung Neoplasms - metabolism
Lung Neoplasms - pathology
Mice
Mice, Nude
Mitogen-Activated Protein Kinases - metabolism
non–small cell lung cancer
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
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Summary: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 (IC 50 70 nmol/L). This result correlates well with the potent antiproliferative activity in erlotinib-resistant NSCLC cell lines (IC 50 120–700 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. [Mol Cancer Ther 2009;8(12):3296–306]
ISSN:1535-7163
1538-8514
DOI:10.1158/1535-7163.MCT-09-0538