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The sensitivity to Hsp90 inhibitors of both normal and oncogenically transformed cells is determined by the equilibrium between cellular quiescence and activity

Pablo C. Echeverria, Kaushik Bhattacharya, Abhinav Joshi, Tai Wang, View ORCID ProfileDidier Picard
doi: https://doi.org/10.1101/472290
Pablo C. Echeverria
Département de Biologie Cellulaire Université de Genève Sciences III, 30, quai Ernest-Ansermet, CH - 1211 Genève 4, Switzerland
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Kaushik Bhattacharya
Département de Biologie Cellulaire Université de Genève Sciences III, 30, quai Ernest-Ansermet, CH - 1211 Genève 4, Switzerland
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Abhinav Joshi
Département de Biologie Cellulaire Université de Genève Sciences III, 30, quai Ernest-Ansermet, CH - 1211 Genève 4, Switzerland
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Tai Wang
Département de Biologie Cellulaire Université de Genève Sciences III, 30, quai Ernest-Ansermet, CH - 1211 Genève 4, Switzerland
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Didier Picard
Département de Biologie Cellulaire Université de Genève Sciences III, 30, quai Ernest-Ansermet, CH - 1211 Genève 4, Switzerland
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  • ORCID record for Didier Picard
  • For correspondence: didier.picard@unige.ch
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Abstract

The molecular chaperone Hsp90 is an essential and highly abundant central node in the interactome of eukaryotic cells. Many of its large number of client proteins are relevant to cancer. A hallmark of Hsp90-dependent proteins is that their accumulation is compromised by Hsp90 inhibitors. Combined with the anecdotal observation that cancer cells may be more sensitive to Hsp90 inhibitors, this has led to clinical trials aiming to develop Hsp90 inhibitors as anti-cancer agents. However, the sensitivity to Hsp90 inhibitors has not been studied in rigorously matched normal versus cancer cells, and despite the discovery of important regulators of Hsp90 activity and inhibitor sensitivity, it has remained unclear, why cancer cells might be more sensitive. To revisit this issue more systematically, we have generated an isogenic pair of normal and oncogenically transformed NIH-3T3 cell lines. Our proteomic analysis of the impact of three chemically different Hsp90 inhibitors shows that these affect a substantial portion of the oncogenic program and that indeed, transformed cells are hypersensitive. Targeting the oncogenic signaling pathway reverses the hypersensitivity, and so do inhibitors of DNA replication, cell growth, translation and energy metabolism. Conversely, stimulating normal cells with growth factors or challenging their proteostasis by overexpressing an aggregation-prone sensitizes them to Hsp90 inhibitors. Thus, the differential sensitivity to Hsp90 inhibitors may not stem from any particular intrinsic difference between normal and cancer cells, but rather from a shift in the balance between cellular quiescence and activity.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted November 16, 2018.
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The sensitivity to Hsp90 inhibitors of both normal and oncogenically transformed cells is determined by the equilibrium between cellular quiescence and activity
Pablo C. Echeverria, Kaushik Bhattacharya, Abhinav Joshi, Tai Wang, Didier Picard
bioRxiv 472290; doi: https://doi.org/10.1101/472290
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The sensitivity to Hsp90 inhibitors of both normal and oncogenically transformed cells is determined by the equilibrium between cellular quiescence and activity
Pablo C. Echeverria, Kaushik Bhattacharya, Abhinav Joshi, Tai Wang, Didier Picard
bioRxiv 472290; doi: https://doi.org/10.1101/472290

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