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Bisphosphonates inactivate human EGFRs to exert antitumor actions.

ABSTRACT: Bisphosphonates are the most commonly prescribed medicines for osteoporosis and skeletal metastases. The drugs have also been shown to reduce cancer progression, but only in certain patient subgroups, suggesting that there is a molecular entity that mediates bisphosphonate action on tumor cells. Using connectivity mapping, we identified human epidermal growth factor receptors (human EGFR or HER) as a potential new molecular entity for bisphosphonate action. Protein thermal shift and cell-free kinase assays, together with computational modeling, demonstrated that N-containing bisphosphonates directly bind to the kinase domain of HER1/2 to cause a global reduction in downstream signaling. By doing so, the drugs kill lung, breast, and colon cancer cells that are driven by activating mutations or overexpression of HER1. Knocking down HER isoforms thus abrogates cell killing by bisphosphonates, establishing complete HER dependence and ruling out a significant role for other receptor tyrosine kinases or the enzyme farnesyl pyrophosphate synthase. Consistent with this finding, colon cancer cells expressing low levels of HER do not respond to bisphosphonates. The results suggest that bisphosphonates can potentially be repurposed for the prevention and therapy of HER family-driven cancers.

SUBMITTER: Yuen T

PROVIDER: S-EPMC4273397 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Bisphosphonates inactivate human EGFRs to exert antitumor actions.

Yuen Tony T Stachnik Agnes A Iqbal Jameel J Sgobba Miriam M Gupta Yogesh Y Lu Ping P Colaianni Graziana G Ji Yaoting Y Zhu Ling-Ling LL Kim Se-Min SM Li Jianhua J Liu Peng P Izadmehr Sudeh S Sangodkar Jaya J Bailey Jack J Latif Yathin Y Mujtaba Shiraz S Epstein Solomon S Davies Terry F TF Bian Zhuan Z Zallone Alberta A Aggarwal Aneel K AK Haider Shozeb S New Maria I MI Sun Li L Narla Goutham G Zaidi Mone M

Proceedings of the National Academy of Sciences of the United States of America 20141201 50

Bisphosphonates are the most commonly prescribed medicines for osteoporosis and skeletal metastases. The drugs have also been shown to reduce cancer progression, but only in certain patient subgroups, suggesting that there is a molecular entity that mediates bisphosphonate action on tumor cells. Using connectivity mapping, we identified human epidermal growth factor receptors (human EGFR or HER) as a potential new molecular entity for bisphosphonate action. Protein thermal shift and cell-free ki ...[more]

PMID: 25453081

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Dataset Information

Bisphosphonates inactivate human EGFRs to exert antitumor actions.

Publications

Bisphosphonates inactivate human EGFRs to exert antitumor actions.

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