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.

Functional Genomics Approaches to Elucidate Vulnerabilities of Intrinsic and Acquired Chemotherapy Resistance

“…Building on this work, the Neely group used HAP1 cells in combination with a CRISPR screening approach (GeCKO.v2 library) to identify resistance-causing loss-of-function mutations against paclitaxel, but extended their efforts to include an additional panel of 26 anticancer drugs. Among others, they identified the previously uncharacterized open reading frame C1orf115, containing a DUF4710 domain of unknown function, to convey robust resistance to paclitaxel, vincristine and the purine analog cladribine [ 161 ], suggesting C1orf115 to be an uncharacterized multidrug resistance gene that escaped previous identification. In contrast, Wei et al used cervical squamous cell carcinoma cells and the GeCKO.v2 library to identify paclitaxel-sensitizing genes.…”

A New Catalog of Structural Variants in 1,301 A. thaliana Lines from Africa, Eurasia, and North America Reveals a Signature of Balancing Selection at Defense Response Genes

“…2016 ), berry color in grapes ( Zhou et al. 2019 ), awn length in basmati rice ( Choi et al. 2020 ), and the loss of the jointed fruit pedicel ( Soyk et al.…”

A Novel circRNA–miRNA–mRNA Hub Regulatory Network in Lung Adenocarcinoma

“…Two miRNAs (hsa-miR-877-5p and hsa-miR-4496) were also included in final ceRNA hub regulatory network. It has been reported that the loss of C1orf115 can lead to the resistance to five anticancer drugs, and the low expression of C1orf115 is related to the poor prognosis of many cancers ( Lau et al, 2020 ). Besides, Senchenko et al (2013) proved that PRICKLE2 was significantly related to the prognosis of various cancers.…”