PRC2-inactivating mutations in cancer enhance cytotoxic response to DNMT1-targeted therapy via enhanced viral mimicry Journal Article
| Authors: | Patel, A. J.; Warda, S.; Maag, J. L. V.; Misra, R.; Miranda-Román, M. A.; Pachai, M. R.; Lee, C. J.; Li, D.; Wang, N.; Bayshtok, G.; Fishinevich, E.; Meng, Y.; Wong, E. W. P.; Yan, J.; Giff, E.; Pappalardi, M. B.; McCabe, M. T.; Fletcher, J. A.; Rudin, C. M.; Chandarlapaty, S.; Scandura, J. M.; Koche, R. P.; Glass, J. L.; Antonescu, C. R.; Zheng, D.; Chen, Y.; Chi, P. |
| Article Title: | PRC2-inactivating mutations in cancer enhance cytotoxic response to DNMT1-targeted therapy via enhanced viral mimicry |
| Abstract: | Polycomb repressive complex 2 (PRC2) has oncogenic and tumor-suppressive roles in cancer. There is clinical success of targeting this complex in PRC2-dependent cancers, but an unmet therapeutic need exists in PRC2-loss cancer. PRC2-inactivating mutations are a hallmark feature of high-grade malignant peripheral nerve sheath tumor (MPNST), an aggressive sarcoma with poor prognosis and no effective targeted therapy. Through RNAi screening in MPNST, we found that PRC2 inactivation increases sensitivity to genetic or small-molecule inhibition of DNA methyltransferase 1 (DNMT1), which results in enhanced cytotoxicity and antitumor response. Mecha-nistically, PRC2 inactivation amplifies DNMT inhibitor–mediated expression of retrotransposons, subsequent viral mimicry response, and robust cell death in part through a protein kinase R (PKR)– dependent double-stranded RNA sensor. Collectively, our observations posit DNA methylation as a safeguard against antitumorigenic cell-fate decisions in PRC2-loss cancer to promote cancer patho-genesis, which can be therapeutically exploited by DNMT1-targeted therapy. SIGNIFICANCE: PRC2 inactivation drives oncogenesis in various cancers, but therapeutically targeting PRC2 loss has remained challenging. Here we show that PRC2-inactivating mutations set up a tumor context–specific liability for therapeutic intervention via DNMT1 inhibitors, which leads to innate immune signaling mediated by sensing of derepressed retrotransposons and accompanied by enhanced cytotoxicity. See related commentary by Guil and Esteller, p. 2020. © 2022 The Authors. |
| Keywords: | signal transduction; controlled study; protein expression; protein phosphorylation; gene mutation; human cell; frameshift mutation; histopathology; nonhuman; tumor associated leukocyte; mouse; phenotype; cell death; cell viability; interleukin 2; breast cancer; cell fate; rna interference; cell differentiation; antineoplastic activity; cytotoxicity; tumor regression; tumor xenograft; dna methylation; carcinogenesis; myelodysplastic syndrome; immune response; transcription regulation; genetic susceptibility; carcinogenicity; immunoblotting; innate immunity; upregulation; genome size; tumor growth; doxycycline; dna methyltransferase; malignant peripheral nerve sheath tumor; fluorescence activated cell sorting; transcriptome; bioluminescence; peripheral blood mononuclear cell; lipocortin 5; double stranded rna; nucleosome; dna methyltransferase 3a; molecularly targeted therapy; retroposon; rna isolation; dna methyltransferase inhibitor; polycomb repressive complex 2; melissa officinalis; inflammasome; tumor spheroid; human; article; nerve sheath; whole exome sequencing; immune signaling; dna (cytosine 5) methyltransferase 1; hexadimethrine bromide |
| Journal Title: | Cancer Discovery |
| Volume: | 12 |
| Issue: | 9 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2022-09-01 |
| Start Page: | 2120 |
| End Page: | 2139 |
| Language: | English |
| DOI: | 10.1158/2159-8290.Cd-21-1671 |
| PUBMED: | 35789380 |
| PROVIDER: | scopus |
| PMCID: | PMC9437570 |
| DOI/URL: | |
| Notes: | Article -- Yeva Fishinevich's first name is listed as "Eve" in publication -- Export Date: 3 October 2022 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work