Lentiviral-based mutagenesis to identify mutations that confer resistance to anti-cancer drugs [lenti]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA691528 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13416213_1.fastq.gz | Fastqsanger.gz | |||
| SRR13416213_2.fastq.gz | Fastqsanger.gz | |||
| SRR13416214_1.fastq.gz | Fastqsanger.gz | |||
| SRR13416214_2.fastq.gz | Fastqsanger.gz | |||
| SRR13416215_1.fastq.gz | Fastqsanger.gz |
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Project description:Identifying resistance mutations in a drug target provides crucial information. Lentiviral transduction creates multiple types of mutations due to the error-prone nature of the HIV-1 reverse transcriptase (RT) and we show this property can be leveraged to identify mutations that confer resistance to targeted anti-cancer drugs, a technique we term “LentiMutate”. First, we improved LentiMutate by making the lentiviral RT more error-prone. Next, we applied this technique to two anti-cancer drugs, imatinib and AMG 510. We find novel deletions in BCR-ABL that confer resistance to BCR-ABL inhibitors and point mutations in the AMG 510 binding pocket or oncogenic non-G12C mutations, in KRAS-G12C or wild-type KRAS, respectively, that confer resistance to AMG 510. LentiMutate may prove highly valuable to clinical and preclinical cancer drug development
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Project description:Lentiviral-based mutagenesis to identify mutations that confer resistance to anti-cancer drugs
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Project description:Identifying resistance mutations in a drug target provides crucial information. Lentiviral transduction creates multiple types of mutations due to the error-prone nature of the HIV-1 reverse transcriptase (RT) and we show this property can be leveraged to identify mutations that confer resistance to targeted anti-cancer drugs, a technique we term “LentiMutate”. First, we improved LentiMutate by making the lentiviral RT more error-prone. Next, we applied this technique to two anti-cancer drugs, imatinib and AMG 510. We find novel deletions in BCR-ABL that confer resistance to BCR-ABL inhibitors and point mutations in the AMG 510 binding pocket or oncogenic non-G12C mutations, in KRAS-G12C or wild-type KRAS, respectively, that confer resistance to AMG 510. LentiMutate may prove highly valuable to clinical and preclinical cancer drug development
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Project description:Lentiviral-based mutagenesis to identify mutations that confer resistance to anti-cancer drugs [umi]
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Project description:Cells were transduced with a lentiviral Lenti-miR library composed of 661 miRNAs (System Biosciences) at a low multiplicity of infection (MOI) such that each cell over-expressed a single miRNA. The transduced population was then injected intra-hepatically into NOD-SCID mice for in vivo selection of miRNAs that when over-expressed, either promoted or suppressed metastatic liver colonization. Genomic DNA PCR amplication and recovery of lenti-viral miRNA inserts was performed on cells prior to injection, and from liver nodules, according to the manufacturer’s protocol. miRNA array profiling allowed for miRNA insert quantification prior to and subsequent to in vivo selection.
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Project description:Cells were transduced with a lentiviral Lenti-miR library composed of 661 miRNAs (System Biosciences) at a low multiplicity of infection (MOI) such that each cell over-expressed a single miRNA. The transduced population was then injected intra-hepatically into NOD-SCID mice for in vivo selection of miRNAs that when over-expressed, either promoted or suppressed metastatic liver colonization. Genomic DNA PCR amplication and recovery of lenti-viral miRNA inserts was performed on cells prior to injection, and from liver nodules, according to the manufacturer’s protocol. miRNA array profiling allowed for miRNA insert quantification prior to and subsequent to in vivo selection.
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Project description:This SuperSeries is composed of the SubSeries listed below.
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Project description:Cells were transduced with a lentiviral Lenti-miR library composed of 661 miRNAs (System Biosciences) at a low multiplicity of infection (MOI) such that each cell over-expressed a single miRNA. The transduced population was then injected intra-hepatically into NOD-SCID mice for in vivo selection of miRNAs that when over-expressed, either promoted or suppressed metastatic liver colonization. Genomic DNA PCR amplication and recovery of lenti-viral miRNA inserts was performed on cells prior to injection, and from liver nodules, according to the manufacturer’s protocol. miRNA array profiling allowed for miRNA insert quantification prior to and subsequent to in vivo selection. To use an unbiased approach to identify regulators of colon cancer metastasis, we transduced a population of colon cancer cells, WiDR, with a lenti-miR library comprising of 661 human miRNAs, such that each individual cells over-express a single miRNA. The heterogenous population is then injected into the liver of immunodeficient mice. We theorized that cells over-expressing miRNAs that modulate colon cancer metastais will have differential representation in the whole population compared to a reference pool of cells. miRNAs that suppressed colon cancer metastasis will be lost in the resulting pool, while miRNAs that promote metastasis will be over-represented compared to the reference pool. Replicate pools of cells were transduced and injected into mice. After a period of 3-5 weeks, liver nodules were taken out and processed for lenti-viral derived miRNA profiling (Post samples) and compared to the reference pool of cells that were not injected into the mice (Pre Samples). The changes in miRNA representation between cells that underwent liver colonization were analyzed.
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Project description:Cells were transduced with a lentiviral Lenti-miR library composed of 661 miRNAs (System Biosciences) at a low multiplicity of infection (MOI) such that each cell over-expressed a single miRNA. The transduced population was then injected intra-hepatically into NOD-SCID mice for in vivo selection of miRNAs that when over-expressed, either promoted or suppressed metastatic liver colonization. Genomic DNA PCR amplication and recovery of lenti-viral miRNA inserts was performed on cells prior to injection, and from liver nodules, according to the manufacturer’s protocol. miRNA array profiling allowed for miRNA insert quantification prior to and subsequent to in vivo selection. To use an unbiased approach to identify regulators of colon cancer metastasis, we transduced a population of colon cancer cells, SW620, with a lenti-miR library comprising of 661 human miRNAs, such that each individual cells over-express a single miRNA. The heterogenous population is then injected into the liver of immunodeficient mice. We theorized that cells over-expressing miRNAs that modulate colon cancer metastais will have differential representation in the whole population compared to a reference pool of cells. miRNAs that suppressed colon cancer metastasis will be lost in the resulting pool, while miRNAs that promote metastasis will be over-represented compared to the reference pool. Replicate pools of cells were transduced and injected into mice. After a period of 3-5 weeks, liver nodules were taken out and processed for lenti-viral derived miRNA profiling (Post samples) and compared to the reference pool of cells that were not injected into the mice (Pre Samples). The changes in miRNA representation between cells that underwent liver colonization were analyzed.
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Project description:Identifying resistance mutations in a drug target provides crucial information. Lentiviral transduction creates multiple types of mutations due to the error-prone nature of the HIV-1 reverse transcriptase (RT). We optimized and leveraged this property to identify drug resistance mutations, a technique we term LentiMutate. After validating this technique by identifying clinically relevant EGFR resistance mutations, we applied this technique to two additional anti-cancer drugs, imatinib and AMG 510. We find novel deletions in BCR-ABL1 that confer resistance to BCR-ABL1 inhibitors and point mutations in the AMG 510 binding pocket or oncogenic non-G12C mutations, in KRAS-G12C or wild-type KRAS, respectively, that confer resistance to AMG 510. LentiMutate may prove highly valuable to clinical and preclinical cancer drug development.
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