Scalera, Stefano; Ricciuti, Biagio; Marinelli, Daniele; Mazzotta, Marco; Cipriani, Laura; Bon, Giulia; Schiavoni, Giulia; ... Maugeri-Saccà, Marcello; + view all Scalera, Stefano; Ricciuti, Biagio; Marinelli, Daniele; Mazzotta, Marco; Cipriani, Laura; Bon, Giulia; Schiavoni, Giulia; Terrenato, Irene; Di Federico, Alessandro; Alessi, Joao V; Fanciulli, Maurizio; Ciuffreda, Ludovica; De Nicola, Francesca; Goeman, Frauke; Caravagna, Giulio; Santini, Daniele; De Maria, Ruggero; Cappuzzo, Federico; Ciliberto, Gennaro; Jamal-Hanjani, Mariam; Awad, Mark M; McGranahan, Nicholas; Maugeri-Saccà, Marcello; - view fewer (2024) Transcriptional phenocopies of deleterious KEAP1 mutations correlate with survival outcomes in lung cancer treated with immunotherapy. Clinical Cancer Research 10.1158/1078-0432.CCR-24-0626. (In press).

Text ccr-24-0626.pdf - Accepted Version Access restricted to UCL open access staff until 10 July 2025. Download (16MB)

Abstract

PURPOSE: Co-occurring mutations in KEAP1 and STK11KRAS have emerged as determinants of survival outcomes in non-small cell lung cancer (NSCLC) patients treated with immunotherapy. However, these mutational contexts identify a fraction of non-responders to immune checkpoint inhibitors. We hypothesized that KEAP1 wild-type tumors recapitulate the transcriptional footprint of KEAP1 mutations, and that this KEAPness phenotype can determine immune responsiveness with higher precision compared to mutation-based models. EXPERIMENTAL DESIGN: The TCGA was used to infer the KEAPness phenotype and explore its immunological correlates at the pan-cancer level. The association between KEAPness and survival outcomes was tested in two independent cohorts of advanced NSCLC patients treated with immunotherapy and profiled by RNA-Seq (SU2C n=153; OAK/POPLAR n=439). The NSCLC TRACERx421 multi-region sequencing study (tumor regions n=947) was used to investigate evolutionary trajectories. RESULTS: KEAPness-dominant tumors represented 50% of all NSCLCs and were associated with shorter progression-free survival (PFS) and overall survival (OS) compared to KEAPness-free cases in independent cohorts of NSCLC patients treated with immunotherapy (SU2C PFS P=0.042, OS P=0.008; OAK/POPLAR PFS P=0.0014, OS P<0.001). Patients with KEAPness tumors had survival outcomes comparable to those with KEAP1-mutant tumors. In the TRACERx421, KEAPness exhibited limited transcriptional intratumoral heterogeneity and immune exclusion, resembling the KEAP1-mutant disease. This phenotypic state occurred across genetically divergent tumors, exhibiting shared and private cancer genes under positive selection when compared to KEAP1-mutant tumors. CONCLUSIONS: We identified a KEAPness phenotype across evolutionary divergent tumors. KEAPness outperforms mutation-based classifiers as a biomarker of inferior survival outcomes in NSCLC patients treated with immunotherapy.

Download activity - last month

Export as CSVJSONXML

Download activity - last 12 months

Export as CSVJSONXML

Downloads by country - last 12 months

Export as XMLJSONCSV

Archive Staff Only

View Item