Molecular cancer therapeutics, 2009-12, Vol.8 (12), p.3296-3306
2009
Details
- Autor(en) / Beteiligte
- Titel
- Targeting heat shock protein 90 with CUDC-305 overcomes erlotinib resistance in non–small cell lung cancer
- Ist Teil von
- Molecular cancer therapeutics, 2009-12, Vol.8 (12), p.3296-3306
- Ort / Verlag
- United States: American Association for Cancer Research
- Erscheinungsjahr
- 2009
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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]
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1535-7163eISSN: 1538-8514DOI: 10.1158/1535-7163.MCT-09-0538Titel-ID: cdi_proquest_miscellaneous_733801888
- Format
- –
- Schlagworte
- 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