The HSP90 Inhibitor NVP-AUY922 Potently Inhibits Non–Small Cell Lung Cancer Growth

Guo

Molecular Cancer Therapeutics

et al. 2016

Oncogenic mutations of KRAS pose a great challenge in the treatment of colorectal cancer. Here we report that mutant KRAS colon cancer cells are nevertheless more susceptible to apoptosis induced by the HSP90 inhibitor AUY922 than those carrying wild-type KRAS. Although AUY922 inhibited HSP90 activity with comparable potency in colon cancer cells irrespective of their KRAS mutational statuses, those with mutant KRAS were markedly more sensitive to AUY922-induced apoptosis. This was associated with upregulation of the BH3-only proteins Bim, Bik, and PUMA. However, only Bim appeared essential, in that knockdown of Bim abolished, whereas knockdown of Bik or PUMA only moderately attenuated apoptosis induced by AUY922. Mechanistic investigations revealed that endoplasmic reticulum (ER) stress was responsible for AUY922-induced upregulation of Bim, which was inhibited by a chemical chaperone or overexpression of GRP78. Conversely, siRNA knockdown of GRP78 or XBP-1 enhanced AUY922-induced apoptosis. Remarkably, AUY922 inhibited the growth of mutant KRAS colon cancer xenografts through activation of Bim that was similarly associated with ER stress. Taken together, these results suggest that AUY922 is a promising drug in the treatment of mutant KRAS colon cancers, and the agents that enhance the apoptosis-inducing potential of Bim may be useful to improve the therapeutic efficacy.

Section: Resultsmentioning

confidence: 92%

Inhibition of HSP90 by AUY922 Preferentially Kills Mutant KRAS Colon Cancer Cells by Activating Bim through ER Stress

Guo

Molecular Cancer Therapeutics

et al. 2016

“…The Hsp90 inhibitor ganetespib, alone or in combination with other anticancer drugs, displays effective antitumor effects in lung cancer cells, especially lung cancer harboring mutant K-Ras (Acquaviva et al, 2012). Another Hsp90 inhibitor, NVP-AUY922 [(5Z)-N-ethyl-5-(4-hydroxy-6-oxo-3-propan-2-ylcyclohexa-2,4-dien-1-ylidene)-4-[4-(morpholin-4-ylmethyl) phenyl]-2H-1,2-oxazole-3-carboxamide], has also shown potent antiproliferative and antitumor effects in various lung cancer cells (Garon et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Synthesis and Evaluation of a Novel Deguelin Derivative, L80, which Disrupts ATP Binding to the C-terminal Domain of Heat Shock Protein 90

et al. 2015

The clinical benefit of current anticancer regimens for lung cancer therapy is still limited due to moderate efficacy, drug resistance, and recurrence. Therefore, the development of effective anticancer drugs for first-line therapy and for optimal second-line treatment is necessary. Because the 90-kDa molecular chaperone heat shock protein (Hsp90) contributes to the maturation of numerous mutated or overexpressed oncogenic proteins, targeting Hsp90 may offer an effective anticancer therapy. Here, we investigated antitumor activities and toxicity of a novel deguelinderived C-terminal Hsp90 inhibitor, designated L80. L80 displayed significant inhibitory effects on the viability, colony formation, angiogenesis-stimulating activity, migration, and invasion of a panel of non-small cell lung cancer cell lines and their sublines with acquired resistance to paclitaxel with minimal toxicity to normal lung epithelial cells, hippocampal cells, vascular endothelial cells, and ocular cells. Biochemical analyses and molecular docking simulation revealed that L80 disrupted Hsp90 function by binding to the C-terminal ATP-binding pocket of Hsp90, leading to the disruption of the interaction between hypoxia-inducible factor (HIF)-1a and Hsp90, downregulation of HIF-1a and its target genes, including vascular endothelial growth factor (VEGF) and insulin-like growth factor 2 (IGF2), and decreased the expression of various Hsp90 client proteins. Consistent with these in vitro findings, L80 exhibited significant antitumor and antiangiogenic activities in H1299 xenograft tumors. These results suggest that L80 represents a novel C-terminal Hsp90 inhibitor with effective anticancer activities with minimal toxicities.

Clinical Cancer Research

“…Indeed, Hsp90a protein was one of 12 proteins used as a panel for lung cancer diagnosis, which were generated by a new aptamer-based proteomic analysis of 1,326 archived serum samples from four independent studies of NSCLC in long-term tobacco-exposed populations (16). Other previous studies showed the HSP90 inhibitor had a potent antitumor activity in in vitro and in vivo models of therapy against NSCLC (17,18). Our current study further demonstrates that detection of plasma Hsp90a protein could be useful as a biomarker for diagnosis of lung cancer and for therapeutic monitoring of responses of patients with lung cancer.…”

Section: Discussionmentioning

confidence: 99%

Plasma Levels of Heat Shock Protein 90 Alpha Associated with Lung Cancer Development and Treatment Responses

Shi

Xiaoqing

Lou

et al. 2014

Purpose: Altered expression of heat shock protein 90 alpha (Hsp90a) was associated with tumor development, progression, and metastasis. This study explored plasma levels of Hsp90a protein in patients with lung cancer and other controls to assess its diagnostic value and monitor treatment responses for patients with lung cancer.Experimental Design: A total of 2,247 individuals were recruited and assigned into two cohorts as static and dynamic groups. ELISA analysis and confirmation of plasma Hsp90a protein levels for association with tumor stages and treatment responses, respectively, were performed.Results: The average plasma levels of Hsp90a protein in patients with lung cancer were significantly higher than in healthy controls (P < 0.0001). Plasma levels of Hsp90a protein in patients with advanced lung cancer (stage III-IV) were higher than in patients with early-stage lung cancer (stage I-II; P < 0.001). Using a cutoff value of 56.33 ng/mL to separate lung cancer from other controls, the sensitivity and specificity reached 72.18% (95% CI, 0.695-0.749) and 78.70% (95% CI, 0.761-0.813), respectively. To confirm the different levels in the second cohort, plasma levels of Hsp90a protein showed a statistically significant difference between preoperative and postoperative patients in surgical patient groups (P < 0.007). There was also a statistically significant difference between the disease progressive group and stable disease group, with regard to partial response after chemotherapy (P < 0.0001).Conclusions: This study demonstrated that plasma Hsp90a protein levels are useful as a diagnostic biomarker in lung cancer and predict the responses of patients with lung cancer to chemotherapy. Clin Cancer Res; 20(23); 6016-22. Ó2014 AACR.