Ponatinib-induced cardiotoxicity is driven by S100A8/A9-NLRP3-IL-1β signaling mediated excessive inflammation
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE220121 | GEO | 2023/02/08
REPOSITORIES: GEO
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Project description:To gain insight into the signaling pathway(s) required for ABL1/ABL2-kinase activity or effected by Ponatinib treatment, we evaluated the consequences of single or double inactivation of ABL1/ABL2 cells, or Ponatinib treated cells on the transcriptome of breast cancer cells. To examine the consequences of depleting the ABL kinases, or Ponatinib treatment on the transcriptome of lung metastatic breast cancer cells we employed next generation sequencing (RNAseq) analysis. We found that 321 genes were significantly differently expressed in Ponatinib treated LM2 cells, and 73 genes were differently expressed in double inactivation of ABL1/ABL2 LM2 cells. However, only about 3.4 percent of Ponatinib affected genes can also be changed by ABL knocking down.
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Project description:Alternative lengthening of telomeres (ALT) supports telomere maintenance and replicative immortality in around 10-15% of cancers, thus representing a compelling target for therapy.To identify anti-cancer drugs that can be repurposed as ALT-centered therapies, we performed for a compound library screen on isogenic cell lines that rely either on telomerase or ALT mechanisms. We validated candidates on a panel of ALT- vs. telomerase-positive sarcoma cells and assessed levels of extrachromosomal telomeric C-circles after drug treatment, as a bona fide marker of ALT activity. We identified a receptor tyrosine kinase inhibitor ponatinib that deregulated ALT mechanisms, increased telomeric replicative stress and induced telomeric dysfunction in ALT cells. Using a model of ALT sarcoma xenografts, we found that ponatinib targeted ALT-positive cells and mitigated telomere elongation in these tumors. To identify the mode of action of ponatinib on ALT, we performed RNA-sequencing and quantitative proteomic and phosphoproteomic analyses, and shortlisted candidates to test the effect of their loss on telomeric C-circle levels. We identified an ABL1-JNK-JUN signalling circuit to be inhibited by ponatinib and to have a role in suppressing extrachromosomal telomeric C-circle formation. Furthermore, transcriptome and interactome analyses of JUN suggested a role of JUN in DNA damage repair pathways, independently of its capacity as a transcription factor. These results were corroborated by new synergistic drug interactions between ponatinib and either DNA synthesis or repair inhibitors such as triciribine and KU-60019, respectively. Overall, we identified a novel signalling pathway impacting ALT which can be targeted by a clinically approved kinase inhibitor.
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