PARP inhibitors (PARPi) have shown remarkable therapeutic efficacy against BRCA1/2-mutant cancers through a synthetic lethal interaction. PARPi exert their therapeutic effects mainly through the blockade of ssDNA damage repair, which leads to the accumulation of toxic DNA double-strand breaks specifically in cancer cells with DNA repair deficiency (BCRAness), including those harboring BRCA1/2 mutations. Here we show that PARPi-mediated modulation of the immune response contributes to their therapeutic effects independently of BRCA1/2 mutations. PARPi promoted accumulation of cytosolic DNA fragments because of unresolved DNA lesions, which in turn activated the DNA-sensing cGAS-STING pathway and stimulated production of type I IFNs to induce antitumor immunity independent of BRCAness. These effects of PARPi were further enhanced by immune checkpoint blockade. Overall, these results provide a mechanistic rationale for using PARPi as immunomodulatory agents to harness the therapeutic efficacy of immune checkpoint blockade. Significance: This work uncovers the mechanism behind the clinical efficacy of PARPi in patients with both BRCAwild-type and BRCA-mutant tumors and provides a rationale for combining PARPi with immunotherapy in patients with cancer.
Adenosine (A) to inosine (I) RNA editing introduces many nucleotide changes in cancer transcriptomes. However, due to the complexity of post-transcriptional regulation, the contribution of RNA editing to proteomic diversity in human cancers remains unclear. Here, we performed an integrated analysis of TCGA genomic data and CPTAC proteomic data. Despite limited site diversity, we demonstrate that A-to-I RNA editing contributes to proteomic diversity in breast cancer through changes in amino acid sequences. We validate the presence of editing events at both RNA and protein levels. The edited COPA protein increases proliferation, migration, and invasion of cancer cells in vitro. Our study suggests an important contribution of A-to-I RNA editing to protein diversity in cancer and highlights its translational potential.
Highlights d We characterize effects of PARP and WEE1 inhibitors on functional proteomics d Concurrent PARP and WEE1 blockade effectively inhibits tumors but is poorly tolerated d Sequential PARP and WEE1 inhibition minimizes toxicity while maintaining efficacy d Basal replication stress influences the therapeutic index of sequential therapy
Poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPis) have shown remarkable therapeutic efficacy against BRCA1/2 mutant cancers through a synthetic lethal interaction. PARPis are believed to exert their therapeutic effects mainly through the blockade of single-strand DNA damage repair, which leads to the accumulation of toxic DNA double strand breaks, specifically in cancer cells with DNA repair deficiency (BCRAness), including those harboring BRCA1/2 mutations.Here, we show that PARPis modulate immune reposes, which contribute to their therapeutic effects independent of BRCA1/2 mutations. The mechanism underlying this PARPi-induced reprogramming of anti-tumor microenvironment involves a promoted accumulation of cytosolic DNA fragments due to unresolved DNA lesions. This in turn activates the DNA sensing cGAS-STING pathway and stimulates production of type I interferons. Ultimately, these events promote PARPi-induced antitumor immunity independent of BRCAness, which can be further enhanced by immune checkpoint blockade. Our results may provide a mechanistic rationale for using PARPis as immunomodulatory agents to harness therapeutic efficacy of immune checkpoint blockade.
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