Acquired resistance to PRMT5 inhibition and the consequent collateral sensitivity to paclitaxel are both Stmn2 dependent
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PROVIDER: PRJNA662553 | ENA |
REPOSITORIES: ENA
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Project description:Drug resistance is a major hurdle for the efficacy of cancer therapies. Protein arginine methyltransferase 5 (PRMT5) is an epigenetic regulator that is upregulated in most tumor types, and PRMT5 inhibitors (PRMT5i) are now in clinical trials. Here we describe the first model of resistance to PRMT5 inhibition, using cell lines derived from murine Kras-G12D;p53-null lung adenocarcinomas (LUAD). Initially, PRMT5 inhibition induced proliferation defects and apoptosis, but eventually we were able to generate numerous independent PRMT5i resistant lines. Resistance was drug-induced, not preexisting, and reflects a novel, shared transcriptional state. This state is stable, and it creates a collateral sensitivity to the taxane, paclitaxel. Accordingly, PRMT5i and paclitaxel synergistically suppress Kras-G12D;p53-null murine LUAD cells. Remarkably, a single gene Stathmin 2 (Stmn2) is required for both PRMT5i resistance and paclitaxel sensitivity. Finally, analysis of TCGA patient data showed that high Stmn2 levels correlates with good tumor responses to taxane treatment.
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Project description:Chemotherapy resistance is a major obstacle to curing cancer patients. Combination drug regimens have shown promise as a method to overcome resistance; however, to date only some cancers have been cured with this method. Collateral sensitivity – the phenomenon whereby resistance to one drug is co-occurrent with sensitivity to a second drug – has been gaining traction as a promising new concept to guide rational design of combination regimens. Here we evolved over 100 subclones of the Eµ-Myc; p19ARF -/- cell line to be resistant to one of four classical chemotherapy agents: doxorubicin, vincristine, paclitaxel, and cisplatin. We then surveyed collateral responses to acquisition of resistance to these agents. Although numerous collateral sensitivities have been documented for antibiotics and targeted cancer therapies, we observed only one collateral sensitivity: half of cell lines that acquired resistance to paclitaxel also acquired a collateral sensitivity to verapamil. However, we found that the mechanism of this collateral sensitivity was unrelated to the mechanism of paclitaxel resistance. Interestingly, we observed heterogeneity in the phenotypic response to acquisition of resistance to most of the drugs we tested, most notably for paclitaxel, suggesting the existence of multiple different states of resistance. Surprisingly, this phenotypic heterogeneity in paclitaxel resistant cell lines was unrelated to transcriptomic heterogeneity among those cell lines. These features of phenotypic and transcriptomic heterogeneity must be taken into account in future studies of treated tumor subclones and in design of chemotherapy combinations.
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Project description:In this work we describe a robust fosfomycin collateral sensitivity phenotype of Pseudomonas aeruginosa resistant mutants selected by antibiotics from different structural families. The underlying mechanism was the reduced expression of the genes encoding the peptidoglycan-recycling pathway, which preserves the peptidoglycan synthesis in situations where the de novo synthesis is blocked, and of fosA, encoding a fosfomycin-inactivating enzyme.
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