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

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

  • Mol Cancer Ther. 2009 Dec;8(12):3296-306. doi: 10.1158/1535-7163.MCT-09-0538.
Rudi Bao 1 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
Affiliations

Affiliation

  • 1 Oncology, Curis, Inc., 45 Moulton Street, Cambridge, MA 02138, USA. [email protected]
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-13469
    99.97%, HSP90 Inhibitor
    HSP