Engineering Forward Genetics into Cultured Cancer Cells for Chemical Target Identification

Povedano, Juan Manuel; Liou, Joel; Wei, David H.; Srivatsav, Ashwin; Kim, Jiwoong; Xie, Yang; Nijhawan, Deepak; McFadden, David G.

doi:10.1016/j.chembiol.2019.06.006

Cited by 16 publications

(31 citation statements)

References 29 publications

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“…Therefore, gaining an understanding of how cancer can become resistant is of significant importance at both the preclinical and clinical stages of drug development. Additionally, resistance pathways can often allude to the underlying mechanism or molecular target of the drug candidate . Our lab has been studying the biological and anticancer activity of rhenium‐based compounds, in part because they are not cross‐resistant with the conventional and widely used platinum‐based drugs .…”

Section: Resultsmentioning

confidence: 99%

“…Additionally,r esistance pathways can often allude to the underlying mechanism or molecular target of the drug candidate. [14][15][16][17][18][19][20] Our lab has been studying the biological and anticancer activity of rhenium-based compounds,i np art because they are not cross-resistant with the conventional and widely used platinum-based drugs. [12,13,[21][22][23] Among the com-pounds that we have investigated, TRIP (Scheme 1) was found to be equally as effective as cisplatin in the A2780 ovarian cancer cell line.F urthermore,T RIP operates via ad istinct mechanism of action by inducing ER stress, activating the UPR pathway,a nd subsequently initiating apoptosis.B yc ontrast, the platinum-based drugs form covalent adducts on DNAa nd inhibit transcription.…”

Section: Development and Characteristics Of The A2780 Trip-resistant mentioning

confidence: 99%

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Exploring Ovarian Cancer Cell Resistance to Rhenium Anticancer Complexes

et al. 2020

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Rhenium tricarbonyl complexes have been recently investigated as novel anticancer agents. However, little is understood about their mechanisms of action, as well as the means by which cancer cells respond to chronic exposure to these compounds. To gain a deeper mechanistic insight into these rhenium anticancer agents, we developed and characterized an ovarian cancer cell line that is resistant to a previously studied compound [Re(CO)3(dmphen)(ptolICN)]+, where dmphen=2,9‐dimethyl‐1,10‐phenanthroline and ptolICN=para‐tolyl isonitrile, called TRIP. This TRIP‐resistant ovarian cancer cell line, A2780TR, was found to be 9 times less sensitive to TRIP compared to the wild‐type A2780 ovarian cancer cell line. Furthermore, the cytotoxicities of established drugs and other rhenium anticancer agents in the TRIP‐resistant cell line were determined. Notably, the drug taxol was found to exhibit a 184‐fold decrease in activity in the A2780TR cell line, suggesting that mechanisms of resistance towards TRIP and this drug are similar. Accordingly, expression levels of the ATP‐binding cassette transporter P‐glycoprotein, an efflux transporter known to detoxify taxol, were found to be elevated in the A2780TR cell line. Additionally, a gene expression analysis using the National Cancer Institute 60 cell line panel identified the MT1E gene to be overexpressed in cells that are less sensitive to TRIP. Because this gene encodes for metallothioneins, this result suggests that detoxification by this class of proteins is another mechanism for resistance to TRIP. The importance of this gene in the A2780TR cell line was assessed, confirming that its expression is elevated in this cell line as well. As the first study to investigate and identify the cancer cell resistance pathways in response to a rhenium complex, this report highlights important similarities and differences in the resistance responses of ovarian cancer cells to TRIP and conventional drugs.

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Section: Resultsmentioning

confidence: 99%

Section: Development and Characteristics Of The A2780 Trip-resistant mentioning

confidence: 99%

Exploring Ovarian Cancer Cell Resistance to Rhenium Anticancer Complexes

et al. 2020

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“…New approaches have recently been developed to address this limitation. For example, genetic ablation of MSH2, a gene involved in MMR pathways, in a number of cancer cell lines can induce higher mutation rates and facilitate selection of drug resistance-conferring alleles 87 . Incorporating these techniques in drug development projects could be particularly valuable for identifying mechanisms of resistance in cancer models with low mutational rates (e.g., childhood retinoblastomas or Ewing sarcomas 88,89 ).…”

Section: 'Crash-testing Drugs'mentioning

confidence: 99%

Chemical strategies to overcome resistance against targeted anticancer therapeutics

Pisa

Kapoor

2020

Nat Chem Biol

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“…Povedana et al used CRISPR/Cas9 to engineer mismatch repair deficiencies in Ewing sarcoma cells and small cell lung cancer cells. They found that deletion of MSH2 results in hypermutations in these normally mutationally silent cells, resulting in the formation of resistant clones in the presence of bortezomib, MLN4924, and CD437, which are all cytotoxic compounds [103]. Recently, Neggers et al reasoned that CRISPR/Cas9-induced non-homologous end-joining repair could be a viable strategy to create a wide variety of functional mutants of essential genes through in-frame mutations.…”

Section: Resistance Cloningmentioning

confidence: 99%

From Phenotypic Hit to Chemical Probe: Chemical Biology Approaches to Elucidate Small Molecule Action in Complex Biological Systems

2020

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Biologically active small molecules have a central role in drug development, and as chemical probes and tool compounds to perturb and elucidate biological processes. Small molecules can be rationally designed for a given target, or a library of molecules can be screened against a target or phenotype of interest. Especially in the case of phenotypic screening approaches, a major challenge is to translate the compound-induced phenotype into a well-defined cellular target and mode of action of the hit compound. There is no “one size fits all” approach, and recent years have seen an increase in available target deconvolution strategies, rooted in organic chemistry, proteomics, and genetics. This review provides an overview of advances in target identification and mechanism of action studies, describes the strengths and weaknesses of the different approaches, and illustrates the need for chemical biologists to integrate and expand the existing tools to increase the probability of evolving screen hits to robust chemical probes.

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Engineering Forward Genetics into Cultured Cancer Cells for Chemical Target Identification

Cited by 16 publications

References 29 publications

Exploring Ovarian Cancer Cell Resistance to Rhenium Anticancer Complexes

Exploring Ovarian Cancer Cell Resistance to Rhenium Anticancer Complexes

Chemical strategies to overcome resistance against targeted anticancer therapeutics

From Phenotypic Hit to Chemical Probe: Chemical Biology Approaches to Elucidate Small Molecule Action in Complex Biological Systems

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