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

Overview of attention for article published in BMC Cancer, July 2015
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Title
P-glycoprotein confers acquired resistance to 17-DMAG in lung cancers with an ALK rearrangement
Published in
BMC Cancer, July 2015
DOI 10.1186/s12885-015-1543-z
Pubmed ID
Authors

Hee Joung Kim, Kye Young Lee, Young Whan Kim, Yun Jung Choi, Jung-Eun Lee, Chang Min Choi, In-Jeoung Baek, Jin Kyung Rho, Jae Cheol Lee

Abstract

Because 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. Resistant 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. The 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. P-gp over-expression is a possible mechanism of acquired resistance to 17-DMAG in cells with ALK rearrangement.

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Mendeley readers

The data shown below were compiled from readership statistics for 15 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 15 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 4 27%
Researcher 3 20%
Student > Doctoral Student 2 13%
Student > Master 1 7%
Student > Bachelor 1 7%
Other 1 7%
Unknown 3 20%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 4 27%
Agricultural and Biological Sciences 3 20%
Medicine and Dentistry 2 13%
Immunology and Microbiology 1 7%
Psychology 1 7%
Other 1 7%
Unknown 3 20%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 28 July 2015.
All research outputs
#3,815,935
of 5,422,321 outputs
Outputs from BMC Cancer
#1,832
of 2,872 outputs
Outputs of similar age
#131,174
of 189,281 outputs
Outputs of similar age from BMC Cancer
#133
of 153 outputs
Altmetric has tracked 5,422,321 research outputs across all sources so far. This one is in the 16th percentile – i.e., 16% of other outputs scored the same or lower than it.
So far Altmetric has tracked 2,872 research outputs from this source. They receive a mean Attention Score of 2.7. This one is in the 20th percentile – i.e., 20% of its peers scored the same or lower than it.
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We're also able to compare this research output to 153 others from the same source and published within six weeks on either side of this one. This one is in the 4th percentile – i.e., 4% of its contemporaries scored the same or lower than it.