Dataset Information

Systematic functional identification of cancer multi-drug resistance genes.

ABSTRACT:

Background

Drug resistance is a major obstacle in cancer therapy. To elucidate the genetic factors that regulate sensitivity to anti-cancer drugs, we performed CRISPR-Cas9 knockout screens for resistance to a spectrum of drugs.

Results

In addition to known drug targets and resistance mechanisms, this study revealed novel insights into drug mechanisms of action, including cellular transporters, drug target effectors, and genes involved in target-relevant pathways. Importantly, we identified ten multi-drug resistance genes, including an uncharacterized gene C1orf115, which we named Required for Drug-induced Death 1 (RDD1). Loss of RDD1 resulted in resistance to five anti-cancer drugs. Finally, targeting RDD1 leads to chemotherapy resistance in mice and low RDD1 expression is associated with poor prognosis in multiple cancers.

Conclusions

Together, we provide a functional landscape of resistance mechanisms to a broad range of chemotherapeutic drugs and highlight RDD1 as a new factor controlling multi-drug resistance. This information can guide personalized therapies or instruct rational drug combinations to minimize acquisition of resistance.

SUBMITTER: Lau MT

PROVIDER: S-EPMC7006212 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Publications

Systematic functional identification of cancer multi-drug resistance genes.

Lau Man-Tat MT Ghazanfar Shila S Parkin Ashleigh A Chou Angela A Rouaen Jourdin R JR Littleboy Jamie B JB Nessem Danielle D Khuong Thang M TM Nevoltris Damien D Schofield Peter P Langley David D Christ Daniel D Yang Jean J Pajic Marina M Neely G Gregory GG

Genome biology 20200207 1

<h4>Background</h4>Drug resistance is a major obstacle in cancer therapy. To elucidate the genetic factors that regulate sensitivity to anti-cancer drugs, we performed CRISPR-Cas9 knockout screens for resistance to a spectrum of drugs.<h4>Results</h4>In addition to known drug targets and resistance mechanisms, this study revealed novel insights into drug mechanisms of action, including cellular transporters, drug target effectors, and genes involved in target-relevant pathways. Importantly, we i ...[more]

PMID: 32028983

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Project description:Platinum-based chemotherapeutic regimens are ultimately unsuccessful due to intrinsic or acquired drug resistance. Understanding the molecular basis for platinum drug sensitivity/resistance is necessary for the development of new drugs and therapeutic regimens. In an effort to identify such determinants, we evaluated the expression of approximately 4000 genes using cDNA microarray screening in a panel of 14 unrelated human ovarian cancer cell lines derived from patients who were either untreated or treated with platinum-based chemotherapy. These data were analysed relative to the sensitivities of the cells to four platinum drugs (cis-diamminedichloroplatinum (cisplatin), carboplatin, DACH-(oxalato)platinum (II) (oxaliplatin) and cis-diamminedichloro (2-methylpyridine) platinum (II) (AMD473)) as well as the proliferation rate of the cells. Correlation analysis of the microarray data with respect to drug sensitivity and resistance revealed a significant association of Stat1 expression with decreased sensitivity to cisplatin (r=0.65) and AMD473 (r=0.76). These results were confirmed by quantitative RT-PCR and Western blot analyses. To study the functional significance of these findings, the full-length Stat1 cDNA was transfected into drug-sensitive A2780 human ovarian cancer cells. The resulting clones that exhibited increased Stat1 expression were three- to five-fold resistant to cisplatin and AMD473 as compared to the parental cells. The effect of inhibiting Jak/Stat signalling on platinum drug sensitivity was investigated using the Janus kinase inhibitor, AG490. Pretreatment of platinum-resistant cells with AG490 resulted in significant increased sensitivity to AMD473, but not to cisplatin or oxaliplatin. Overall, the results indicate that cDNA microarray analysis may be used successfully to identify determinants of drug sensitivity/resistance and future functional studies of other candidate genes from this database may lead to an increased understanding of the drug resistance phenotype.

Dataset Information

Systematic functional identification of cancer multi-drug resistance genes.

Background

Results

Conclusions

Publications

Systematic functional identification of cancer multi-drug resistance genes.

Similar Datasets

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