Identification of a transporter complex responsible for the cytosolic entry of nitrogen-containing bisphosphonates

Yu, Zhou; Surface, Lauren E.; Park, Chong Yon; Horlbeck, Max A.; Wyant, Gregory A.; Abu-Remaileh, Monther; Peterson, Timothy R.; Sabatini, David M.; Weissman, Jonathan S.; O’Shea, Erin K.

doi:10.7554/elife.36620

Cited by 46 publications

(65 citation statements)

References 26 publications

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“…Transmembrane transporters represent a major class of metabolic genes involved in several cellular processes affecting drug potency and activity, including the uptake and extrusion of these xenobiotic compounds 2 . In the past, the discovery of specific transporters for several cytotoxic compounds by insertional mutagenesis and CRISPR/Cas9-based screens had provided clear examples of the power of genetic approaches for the identification of such relationships [20][21][22]49 . However, despite the unambiguous involvement of these transporters in drug uptake, it is possible that these relationships are exceptional in nature and confined to particular chemical subtypes.…”

Section: Discussionmentioning

confidence: 99%

A widespread role for SLC transmembrane transporters in resistance to cytotoxic drugs

Gottardi

César-Razquin

Παπακώστας

et al. 2019

Preprint

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The activity and potency of a drug is inherently affected by the metabolic state of its target cell.Solute Carriers (SLCs) represent the largest family of transmembrane transporters in humans and constitute major determinants of cellular metabolism. Several SLCs have been shown to be required for the uptake of individual chemical compounds into cellular systems, but systematic surveys of transporter-drug relationships in human cells are currently lacking. We performed a series of genetic screens in the haploid human cell line HAP1 using a set of 60 cytotoxic compounds representative of the chemical space populated by approved drugs. By using a SLC-focused CRISPR/Cas9 lentiviral library, we identified transporters whose absence induced resistance to the drugs tested. Among the hundreds of drug-SLC relationships identified, we confirmed the role of the folate transporter SLC19A1 on the activity of antifolates and of SLC29A1 on several nucleoside analogs. Among the newly discovered dependencies, we identified the transporters SLC11A2/SLC16A1 for artemisinin derivatives and SLC35A2/SLC38A5 for cisplatin. The functional dependence on SLCs observed for a significant proportion of the compounds screened suggested a widespread role for SLCs in the uptake and cellular activity of cytotoxic drugs and provided an experimentally validated set of SLC-drug associations for a number of clinically relevant compounds.

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Section: Discussionmentioning

confidence: 99%

A widespread role for SLC transmembrane transporters in resistance to cytotoxic drugs

Gottardi

César-Razquin

Παπακώστας

et al. 2019

Preprint

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“…The sgRNA vectors for validation experiments are listed in the Key Resources table; sgRNAs were selected based on their inclusion in the GI map, their activity score, or, for cholesterol biosynthesis genes, their alendronate resistance or sensitivity phenotype from (Yu et al, 2018). Briefly, cells were co- transduced at ~5-60% infection with two lentiviral vectors marked with either BFP or GFP each encoding a single sgRNA.…”

Section: Star Methodsmentioning

confidence: 99%

“…Briefly, we used the ScreenProcessing analysis pipeline (github.com/mhorlbeck/ScreenProcessing) to process and normalize CRISPRi data for genes that modulate response to alendronate from Yu et al (Gilbert et al, 2014; Horlbeck et al, 2016a; Yu et al, 2018). We extracted data relating to DNA repair genes and deoxynucleotide synthesis from this dataset (Table S7).…”

Section: Star Methodsmentioning

confidence: 99%

Mapping the Genetic Landscape of Human Cells

Horlbeck

Wang

et al. 2018

Cell

266

241

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Seminal yeast studies have established the value of comprehensively mapping genetic interactions (GIs) for inferring gene function. Efforts in human cells using focused gene sets underscore the utility of this approach, but the feasibility of generating large-scale, diverse human GI maps remains unresolved. We developed a CRISPR interference platform for large-scale quantitative mapping of human GIs. We systematically perturbed 222,784 gene pairs in two cancer cell lines. The resultant maps cluster functionally related genes, assigning function to poorly characterized genes, including TMEM261, a new electron transport chain component. Individual GIs pinpoint unexpected relationships between pathways, exemplified by a specific cholesterol biosynthesis intermediate whose accumulation induces deoxynucleotide depletion, causing replicative DNA damage and a synthetic-lethal interaction with the ATR/9-1-1 DNA repair pathway. Our map provides a broad resource, establishes GI maps as a high-resolution tool for dissecting gene function, and serves as a blueprint for mapping the genetic landscape of human cells.

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“…Recently we identified another gene, SL37A3, that provides molecular details for how ATRAID connects to the N-BPs and FDPS 36 . However, because SLC37A3 wasn't amongst the 30 genes that scored in all the patient-and cell-based studies (Fig.…”

mentioning

confidence: 99%

“…1g). Using CRISPRi, we identified both ATRAID and FDPS among the top 200 hits with alendronate 36 , but not with several other clinical and experimental drugs including ones that regulate the mevalonate pathway ( Fig. 1h and Supplementary Table 1a) [37][38][39] .…”

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confidence: 99%

ATRAIDregulates the action of nitrogen-containing bisphosphonates on bone

Surface

Burrow²,

Park³

et al. 2018

Preprint

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. CC-BY-NC-ND 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/338350 doi: bioRxiv preprint first posted online Jun. 4, 2018; 3 Nitrogen-containing bisphosphonates (N-BPs) are the standard treatment for osteoporosis and several other bone diseases 11,12 . Certain N-BPs (pamidronate (Aredia®), zoledronate (Zometa®)) are also routinely prescribed to prevent skeletal complications in patients with multiple myeloma and with bone metastases from other malignancies, including breast and prostate cancer 13 . However, because N-BPs cause rare yet serious side-effects, such as atypical fractures and osteonecrosis of the jaw, many patients avoid taking them [5][6][7]11 , causing the number of prescriptions to plummet over 50% in the last decade 7,14 . Thus, there is a sizeable and growing need to better understand the genetic factors that might underlie the onand off-target clinical effects of the N-BPs.A goal of personalized medicine is to identify biomarkers that underlie drug responsiveness. In the case of the N-BPs, it can be said that there are limited personalization options owing to the limited number of genes implicated in the mechanism of action of N-BPs on bone. was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/338350 doi: bioRxiv preprint first posted online Jun. 4, 2018; 4 understanding of the molecular mechanisms by which N-BPs regulate the major bone cell types would be improved by further studies.To provide insight into the mechanism(s) of N-BPs action, we performed a genetic screen to identify human genes required for the anti-proliferative effects of N-BPs (Fig. 1a) Other genes identified in our alendronate haploid screen (SNTG1, PLCL1, and EPHB1) have been previously connected to N-BP action on bone cells and/or human bone diseases [28][29][30] . To systematically evaluate all "hits" we identified (i.e., the 185 genes with FDR p-value < 0.05, see Fig. 1b), we developed a computational approach utilizing a molecular biology-optimized version of PubMed (currently at ~27M records) to assess to what extent our haploid screen identified genes were cited as relevant to human studies that focus on bone (see "PubMed citation analysis" in the Methods section for details). We asked whether our alendronate haploid screen hits were mentioned in publications co-occurring with the term "bone" vs. other tissues along with identifiers of genome-wide screening, namely the strings, "GWAS" or "genome-wide" (Fig. 1c). Indeed, our alendronate screen hits were enriched in publications co-mentioning "bone" and genome-wide studies compared to control gene sets (Fig. 1d, Supplementary Table 1b). This . CC-BY-NC-ND 4.0 International license It is made available under a was not peer-reviewed...

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Identification of a transporter complex responsible for the cytosolic entry of nitrogen-containing bisphosphonates

Cited by 46 publications

References 26 publications

A widespread role for SLC transmembrane transporters in resistance to cytotoxic drugs

A widespread role for SLC transmembrane transporters in resistance to cytotoxic drugs

Mapping the Genetic Landscape of Human Cells

ATRAIDregulates the action of nitrogen-containing bisphosphonates on bone

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