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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

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Published in PLOS ONE. 2019, vol. 14, no. 2, p. e0208287
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 gen- erated 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 hypersen- sitivity, and so do inhibitors of DNA replication, cell growth, translation and energy metabo- lism. 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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Research group Groupe Picard
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ECHEVERRIA, Pablo Christian et al. The sensitivity to Hsp90 inhibitors of both normal and oncogenically transformed cells is determined by the equilibrium between cellular quiescence and activity. In: PLOS One, 2019, vol. 14, n° 2, p. e0208287. https://archive-ouverte.unige.ch/unige:114495

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Deposited on : 2019-02-22

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