Transcriptional phenocopies of deleterious KEAP1 mutations correlate with survival outcomes in lung cancer treated with immunotherapy

免疫疗法 肺癌 癌症 生物 物候学 肿瘤科 表型 生存分析 STK11段 内科学 癌症研究 医学 基因 克拉斯 遗传学 结直肠癌
作者
Stefano Scalera,Biagio Ricciuti,Daniele Marinelli,Marco Mazzotta,Laura Cipriani,Giulia Bon,Giulia Schiavoni,Irene Terrenato,Alessandro Di Federico,Joao V. Alessi,Maurizio Fanciulli,Ludovica Ciuffreda,Francesca De Nicola,Frauke Goeman,Giulio Caravagna,Daniele Santini,Ruggero De Maria,Federico Cappuzzo,Gennaro Ciliberto,Mariam Jamal‐Hanjani
出处
期刊:Clinical Cancer Research [American Association for Cancer Research]
卷期号:30 (19): 4397-4411
标识
DOI:10.1158/1078-0432.ccr-24-0626
摘要

Co-occurring mutations in KEAP1 and STK11/KRAS have emerged as determinants of survival outcomes in patients with non-small cell lung cancer (NSCLC) treated with immunotherapy. However, these mutational contexts identify a fraction of nonresponders 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. The Cancer Genome Atlas 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 patients with advanced NSCLC treated with immunotherapy and profiled by RNA sequencing (SU2C n = 153; OAK/POPLAR n = 439). The NSCLC TRACERx421 multiregion sequencing study (tumor regions, n = 947) was used to investigate evolutionary trajectories. 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 patients with NSCLC 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. We identified a KEAPness phenotype across evolutionary divergent tumors. KEAPness outperforms mutation-based classifiers as a biomarker of inferior survival outcomes in patients with NSCLC treated with immunotherapy.
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