| First Author | Marzio A | Year | 2022 |
| Journal | Cell | Volume | 185 |
| Issue | 1 | Pages | 169-183.e19 |
| PubMed ID | 34963055 | Mgi Jnum | J:319532 |
| Mgi Id | MGI:6864213 | Doi | 10.1016/j.cell.2021.12.005 |
| Citation | Marzio A, et al. (2022) EMSY inhibits homologous recombination repair and the interferon response, promoting lung cancer immune evasion. Cell 185(1):169-183.e19 |
| abstractText | Non-small cell lung cancers (NSCLCs) harboring KEAP1 mutations are often resistant to immunotherapy. Here, we show that KEAP1 targets EMSY for ubiquitin-mediated degradation to regulate homologous recombination repair (HRR) and anti-tumor immunity. Loss of KEAP1 in NSCLC induces stabilization of EMSY, producing a BRCAness phenotype, i.e., HRR defects and sensitivity to PARP inhibitors. Defective HRR contributes to a high tumor mutational burden that, in turn, is expected to prompt an innate immune response. Notably, EMSY accumulation suppresses the type I interferon response and impairs innate immune signaling, fostering cancer immune evasion. Activation of the type I interferon response in the tumor microenvironment using a STING agonist results in the engagement of innate and adaptive immune signaling and impairs the growth of KEAP1-mutant tumors. Our results suggest that targeting PARP and STING pathways, individually or in combination, represents a therapeutic strategy in NSCLC patients harboring alterations in KEAP1. |
