P-glycoprotein confers acquired resistance to 17-DMAG in lung cancers with an ALK rearrangement

BMC Cancer

Research Article

In-Jeoung Baek¹  Young Whan Kim²  Kye Young Lee³  Hee Joung Kim³  Jae Cheol Lee⁴  Jung-Eun Lee⁵  Yun Jung Choi⁵  Jin Kyung Rho⁶  Chang Min Choi⁷ 

[1] Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea;Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Seoul National University College of Medicine, Seoul, South Korea;Department of Internal Medicine, Konkuk University Medical Center, Seoul, South Korea;Department of Oncology, Asan Medical Center, College of Medicine, University of Ulsan, 86 Asanbyeongwon-gil, 138-736, Songpa-gu, Seoul, South Korea;Department of Pulmonary and Critical Care Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea;Department of Pulmonary and Critical Care Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea;Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea;Department of Pulmonary and Critical Care Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea;Department of Oncology, Asan Medical Center, College of Medicine, University of Ulsan, 86 Asanbyeongwon-gil, 138-736, Songpa-gu, Seoul, South Korea;

关键词: Lung cancer;    ALK;    Heat shock protein 90;    Resistance;    P-glycoprotein;   

DOI  :  10.1186/s12885-015-1543-z

 received in 2015-01-12, accepted in 2015-07-14,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundBecause anaplastic lymphoma kinase (ALK) is dependent on Hsp90 for protein stability, Hsp90 inhibitors are effective in controlling growth of lung cancer cells with ALK rearrangement. We investigated the mechanism of acquired resistance to 17-(Dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), a geldanamycin analogue Hsp90 inhibitor, in H3122 and H2228 non-small cell lung cancer cell lines with ALK rearrangement.MethodsResistant cell lines (H3122/DR-1, H3122/DR-2 and H2228/DR) were established by repeated exposure to increasing concentrations of 17-DMAG. Mechanisms for resistance by either NAD(P)H/quinone oxidoreductase 1 (NQO1), previously known as a factor related to 17-DMAG resistance, or P-glycoprotein (P-gp; ABCB1/MDR1) were queried using RT-PCR, western blot analysis, chemical inhibitors, the MTT cell proliferation/survival assay, and cellular efflux of rhodamine 123.ResultsThe resistant cells showed no cross-resistance to AUY922 or ALK inhibitors, suggesting that ALK dependency persists in cells with acquired resistance to 17-DMAG. Although expression of NQO1 was decreased in H3122/DR-1 and H3122/DR-2, NQO1 inhibition by dicumarol did not affect the response of parental cells (H2228 and H3122) to 17-DMAG. Interestingly, all resistant cells showed the induction of P-gp at the protein and RNA levels, which was associated with an increased efflux of the P-gp substrate rhodamine 123 (Rho123). Transfection with siRNA directed against P-gp or treatment with verapamil, an inhibitor of P-gp, restored the sensitivity to the drug in all cells with acquired resistance to 17-DMAG. Furthermore, we also observed that the growth-inhibitory effect of 17-DMAG was decreased in A549/PR and H460/PR cells generated to over-express P-gp by long-term exposure to paclitaxel, and these cells recovered their sensitivity to 17-DMAG through the inhibition of P-gp.ConclusionP-gp over-expression is a possible mechanism of acquired resistance to 17-DMAG in cells with ALK rearrangement.

【 授权许可】

Unknown   
© Kim et al. 2015. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.