Mitochondrial metabolism promotes adaptation to proteotoxic stress

Tsvetkov, Peter; Detappe, Alexandre; Cai, Kai; Keys, Heather R.; Brune, Zarina; Ying, Weiwen; Thiru, Prathapan; Reidy, Mairéad; Kugener, Guillaume; Rossen, Jordan; Kocak, Mustafa; Kory, Nora; Tsherniak, Aviad; Santagata, Sandro; Whitesell, Luke; Ghobrial, Irène M.; Markley, John L.; Lindquist, Susan; Golub, Todd R.

doi:10.1038/s41589-019-0291-9

Cited by 337 publications

(336 citation statements)

References 60 publications

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“…Our finding that the metallothionein-encoding genes MT1E and MT2A on 16q are predictive of disulfiram activity is mechanistically plausible: disulfiram's activity is copper-dependent, and MT1E and MT2A are known metal-chelating proteins 22 . Consistent with this observation, MT1E and MT2A expression was also correlated with sensitivity to thiram and elesclomol, other copper-binding compounds 23,24 . In addition, disulfiram has been reported to induce metallothionein gene expression in prostate cancer cells 25 .…”

Section: Inducers Of Pde3a-slfn12 Protein-protein Interactionsupporting

confidence: 74%

Discovering the anticancer potential of non-oncology drugs by systematic viability profiling

et al. 2020

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Anticancer uses of non-oncology drugs have occasionally been found, but such discoveries have been serendipitous. We sought to create a public resource containing the growth-inhibitory activity of 4,518 drugs tested across 578 human cancer cell lines. We used PRISM (profiling relative inhibition simultaneously in mixtures), a molecular barcoding method, to screen drugs against cell lines in pools. An unexpectedly large number of non-oncology drugs selectively inhibited subsets of cancer cell lines in a manner predictable from the molecular features of the cell lines. Our findings include compounds that killed by inducing phosphodiesterase 3A-Schlafen 12 complex formation, vanadium-containing compounds whose killing depended on the sulfate transporter SLC26A2, the alcohol dependence drug disulfiram, which killed cells with low expression of metallothioneins, and the anti-inflammatory drug tepoxalin, which killed via the multidrug resistance protein ATP-binding cassette subfamily B member 1 (ABCB1). The PRISM drug repurposing resource (https://depmap.org/repurposing) is a starting point to develop new oncology therapeutics, and more rarely, for potential direct clinical translation. NATURE CANCER | VOL 1 | FeBRUARY 2020 | 235-248 | www.nature.com/natcancer 235 ResouRce NATuRE CANCER the remaining compounds being either chemotherapeutics (2%) or targeted oncology agents (21%).Screening results. We employed a 2-stage screening strategy whereby drugs were first screened in triplicate at a single dose (2.5 µM); 1,448 drugs screening positives were then rescreened in triplicate in an eight-point dose-response ranging from 10 µM to 610 pM ( Fig. 1c and Supplementary Table 2). Interestingly, most active compounds (774 out of 1,448, 53%) were originally developed for non-oncology clinical indications (Fig. 1d). The primary and secondary screening datasets are available on the Cancer Dependency Map portal (https://depmap.org/repurposing) and figshare (https://doi.org/10.6084/m9.figshare.9393293; Extended Data Figs. 1-4). We compared the PRISM results to two gold standard datasets: GDSC (ref. 2 ) and CTD 2 (ref. 3 ). The three datasets shared 84 compounds tested on a median of 236 common cell lines, yielding 16,650 shared data points. The PRISM dataset had a similar degree of concordance to GDSC and CTD 2 (Pearson correlations of 0.60 and 0.61, respectively over all shared data points), as the GDSC and CTD 2 datasets had to each other (Pearson correlation 0.62) (Extended Data Fig. 5a). The three datasets remained similarly concordant when the analysis was restricted to data points showing evidence of anticancer activity (Extended Data Fig. 5b). We conclude that, despite differences in assay format, sources of compounds 5 and sources of cell lines 6 , the PRISM Repurposing dataset is similarly robust compared to existing pharmacogenomic datasets.At the level of individual compound dose-responses, we note that the PRISM Repurposing dataset tends to be somewhat noisier, with a higher standard error estimated from vehicle contr...

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Section: Inducers Of Pde3a-slfn12 Protein-protein Interactionsupporting

confidence: 74%

Discovering the anticancer potential of non-oncology drugs by systematic viability profiling

et al. 2020

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“…Our finding that the metallothionein genes MT1E and MT2A on 16q are predictive of disulfiram activity is mechanistically plausible, given that disulfiram's activity is copper-dependent, and MT1E and MT2A are known metal-chelating proteins 19 . Consistent with this observation, MT1E and MT2A expression was also correlated with sensitivity to thiram and elesclomol, other copper-binding compounds 20,21 . In addition, disulfiram has been reported to induce metallothionein gene expression in prostate cancer cells 22 .…”

Section: Predictive Biomarkers Of Disulfiram Activitysupporting

confidence: 74%

Non-oncology drugs are a source of previously unappreciated anti-cancer activity

Corsello

et al. 2019

Preprint

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Anti-cancer uses of non-oncology drugs have been found on occasion, but such discoveries have been serendipitous and rare. We sought to create a public resource containing the growth inhibitory activity of 4,518 drugs tested across 578 human cancer cell lines. To accomplish this, we used PRISM, which involves drug treatment of molecularly barcoded cell lines in pools. Relative barcode abundance following treatment thus reflects cell line viability. We found that an unexpectedly large number of non-oncology drugs selectively inhibited subsets of cancer cell lines. Moreover, the killing activity of the majority of these drugs was predictable based on the molecular features of the cell lines. Follow-up of several of these compounds revealed novel mechanisms. For example, compounds that kill by inducing PDE3A-SLFN12 complex formation; vanadium-containing compounds whose killing is dependent on the sulfate transporter SLC26A2; the alcohol dependence drug disulfiram, which kills cells with low expression of metallothioneins; and the anti-inflammatory drug tepoxalin, whose killing is dependent on high expression of the multi-drug resistance gene ABCB1. These results illustrate the potential of the PRISM drug repurposing resource as a starting point for new oncology therapeutic development. The resource is available at https://depmap.org.

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“…6i). Recently, it has been proposed that PI resistance can be overcome by targeting mitochondrial biology 45,46 . Interestingly, venetoclax, which targets mitochondria to induce apoptosis, also strongly synergized with E7107, potentially indicating some cross-talk between these mechanisms of anti-MM action (Fig.…”

Section: Srsf1 Phosphomimetic Has Weakened Spliceosome Interactionmentioning

confidence: 99%

Proteasome inhibitor-induced modulation reveals the spliceosome as a specific therapeutic vulnerability in multiple myeloma

et al. 2020

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Enhancing the efficacy of proteasome inhibitors (PI) is a central goal in myeloma therapy. We proposed that signaling-level responses after PI may reveal new mechanisms of action that can be therapeutically exploited. Unbiased phosphoproteomics after treatment with the PI carfilzomib surprisingly demonstrates the most prominent phosphorylation changes on splicing related proteins. Spliceosome modulation is invisible to RNA or protein abundance alone. Transcriptome analysis after PI demonstrates broad-scale intron retention, suggestive of spliceosome interference, as well as specific alternative splicing of protein homeostasis machinery components. These findings lead us to evaluate direct spliceosome inhibition in myeloma, which synergizes with carfilzomib and shows potent anti-tumor activity. Functional genomics and exome sequencing further support the spliceosome as a specific vulnerability in myeloma. Our results propose splicing interference as an unrecognized modality of PI mechanism, reveal additional modes of spliceosome modulation, and suggest spliceosome targeting as a promising therapeutic strategy in myeloma.

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Mitochondrial metabolism promotes adaptation to proteotoxic stress

Cited by 337 publications

References 60 publications

Discovering the anticancer potential of non-oncology drugs by systematic viability profiling

Discovering the anticancer potential of non-oncology drugs by systematic viability profiling

Non-oncology drugs are a source of previously unappreciated anti-cancer activity

Proteasome inhibitor-induced modulation reveals the spliceosome as a specific therapeutic vulnerability in multiple myeloma

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