Strong anti-tumor effect of NVP-AUY922, a novel Hsp90 inhibitor, on non-small cell lung cancer

Our plain-English summary of Strong anti-tumor effect of NVP-AUY922, a novel Hsp90 inhibitor, on non-small cell lung cancer, by T. Ueno, K. Tsukuda, S. Toyooka, et al (Lung Cancer, 2012).

The study

• Authors: T. Ueno, K. Tsukuda, S. Toyooka, M. Ando, M. Takaoka, J. Soh, H. Asano, Y. Maki, T. Muraoka, N. Tanaka, K. Shien, M. Furukawa, T. Yamatsuji, K. Kiura, Y. Naomoto, S. Miyoshi
• Journal: Lung Cancer
• Published: 2012;76(1):26-31
• Cited by: 38 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

The anti-tumor activity of a newly developed Hsp90 inhibitor, NVP-AUY922 (AUY922), against non-small cell lung cancer (NSCLC) was examined. Twenty-one NSCLC cell lines were used, the somatic alterations of which were characterized. Cell proliferation was analyzed using a modified MTS assay. Expression of the client proteins was assessed using Western blotting. The cell cycle was analyzed using flow cytometry. The IC50 value of AUY922 for the NSCLC cell lines ranged from 5.2 to 860 nM (median, 20.4 nM). Based on previous data, cells with an IC50 of less than 50 nM were classified as sensitive cells and 19 of the 21 NSCLC cell lines were judged to be sensitive. The IC50 of five malignant pleural mesothelioma (MPM) cell lines revealed that the MPM cells had a significantly higher IC50 value (median, 89.2 nM; range, 22.2-24,100 nM) than the NSCLC cells (p=0.015). There was significant depletion of both the total and phosphorylated client proteins--EGFR, MET, HER2 and AKT--at low drug concentrations (50-100 nM) in drug-sensitive cell lines. Cell-cycle analysis was performed for two sensitive cell lines, H1975 and H838. Following AUY922 treatment, an increase in the sub-G0-G1 cell population, as well as appearance of cleaved PARP expression, indicated the induction of apoptosis. In conclusion, AUY922 was effective against most NSCLC cell lines, independent of the type of known molecular alteration, and appears to be a promising new drug for the treatment of NSCLC.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

In plain English

This laboratory study used cancer cells grown in dishes; asbestos exposure was not studied. The authors tested an experimental drug, NVP-AUY922 (AUY922), which blocks a protein called Hsp90, on 21 non-small cell lung cancer (NSCLC) cell lines and five malignant pleural mesothelioma (MPM) cell lines. They measured the drug concentration needed to halve cell growth (the IC50). This ranged from 5.2 to 860 nM in the lung cancer lines and from 22.2 to 24,100 nM in the mesothelioma lines, a statistically significant difference (p = 0.015). Using a 50 nM cut-off, 19 of 21 lung cancer lines and two of five mesothelioma lines were classed as sensitive. In sensitive lung cancer lines, the drug depleted several growth-related proteins at 50 nM. It also induced cell death (apoptosis) in the two lines tested for this. The authors concluded that AUY922 was effective against most NSCLC lines regardless of their known genetic changes. They also concluded that their results suggested it is not effective in MPM compared with NSCLC.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: laboratory (in vitro) cell line experiment
• Who was studied: 21 human non-small cell lung cancer cell lines with various genetic alterations and 5 malignant pleural mesothelioma cell lines, mostly established at the US National Cancer Institute and the University of Texas Southwestern, plus one breast cancer line (SKBR3) used to check the method
• Exposure: The Hsp90-inhibiting drug NVP-AUY922 (AUY922), obtained from Novartis, applied to cells at a range of concentrations starting from 0 (control); no asbestos or fiber exposure was studied
• Main results:
  • IC50 (drug concentration halving cell growth) ranged from 5.2 to 860 nM in the NSCLC cell lines and from 22.2 to 24,100 nM in the MPM cell lines; the difference was statistically significant (p = 0.015)
  • Median IC50 in the five MPM cell lines was 89.2 nM
  • With sensitivity defined as an IC50 below 50 nM, 19 of 21 NSCLC cell lines and 2 of 5 MPM cell lines were sensitive (p = 0.034)
  • In the NSCLC lines, the drug inhibited growth of lines with wild-type EGFR, K-ras mutation, EML4-ALK fusion gene or other genetic alterations, as well as lines with EGFR mutations
  • Two NSCLC cell lines, H1395 and Calu3, were resistant
  • In sensitive NSCLC cell lines, client proteins including EGFR, MET, HER2, AKT and Cyclin D1 were depleted after treatment with 50 nM AUY922
  • In two sensitive NSCLC cell lines (H1975 and H838), the drug induced apoptosis (cell death)
• The authors' conclusion: The authors concluded that AUY922 was effective against most NSCLC cell lines, independent of the type of known molecular alteration. They stated that their results suggest AUY922 is not effective in MPM compared with NSCLC.
• Limitations the authors state:
  • The authors stated that the mechanism of resistance in the resistant NSCLC lines was unclear, and that selecting patients for the drug on the basis of molecular properties may be difficult
  • The authors stated that the precise mechanism of resistance in mesothelioma cells is not clear

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Non-Small Cell Lung Cancer, Pleural Mesothelioma, EGFR, HER2, Apoptosis.

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