debio-0932 and Lung-Neoplasms

Debio0932 is a promising lead compound in phase I clinical trials targeting the N-terminal ATP-binding pocket of the molecular chaperone heat-shock protein 90 (Hsp90

Topics: A549 Cells; Antineoplastic Agents; Benzodioxoles; Binding Sites; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; HSP90 Heat-Shock Proteins; Humans; Imidazoles; Lung Neoplasms; Molecular Dynamics Simulation; Protein Binding

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.

Topics: Animals; Apoptosis; Benzodioxoles; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Synergism; Erlotinib Hydrochloride; Female; HSP90 Heat-Shock Proteins; Humans; Imidazoles; Lung Neoplasms; Mice; Mice, Nude; Mitogen-Activated Protein Kinases; Paclitaxel; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Quinazolines; Signal Transduction; Survival Analysis; Tumor Burden; Xenograft Model Antitumor Assays