SMARCA4, STK11, and KEAP1 co-inactivation associates with poor prognosis and upregulation of the TGF-β pathway in lung adenocarcinoma
Abstract
BackgroundLung adenocarcinoma (LUAD) is clinically and molecularly defined by oncogenic driver mutations, identification of which has led to the development of driver-targeted therapies and substantial improvements in prognosis for subsets of LUAD patients. Recent studies assessing clinical outcomes in the context of multigenic alterations have identified secondary mutations that might explain differential responses to targeted therapies, chemotherapies and immunotherapies. Genetic inactivation or loss of SMARCA4, which frequently co-occurs with loss-of-function mutations in STK11 and KEAP1, is especially predictive of poor prognosis and shorter overall survival in LUAD patients, regardless of driver status. We sought to examine the clinical and functional associations of SMARCA4 deficiency in LUAD, with or without co-associated STK11/KEAP1 loss-of-function. MethodsWe examined correlation between SMARCA4 loss, gene expression and prognosis through genomic and transcriptomic profiling of clinically annotated LUAD samples. We generated isogenic cell line models with genetic knockouts of SMARCA4 with or without concomitant STK11 and KEAP1 to profile mutationally-defined genotypes of interest in vitro and in vivo. Lastly, we interrogated the functional dependency of SMARCA4/STK11/KEAP1 triple mutant models on TGF-{beta} signaling to assess its potential as a therapeutic target. ResultsSMARCA4/STK11/KEAP1 triple mutant LUAD is associated with poor survival and high frequency of multisite metastasis. SMARCA4/STK11/KEAP1 triple knockout models showed enhanced migration and invasion in vitro, and diversified organotropism in an in vivo intracardiac xenograft metastasis assay. RNA-Seq and DNaseI-Seq of these in vitro models and clinical samples identified upregulation of TGF-{beta} signaling and EMT gene expression signatures, and corresponding changes in chromatin accessibility, in SMARCA4/STK11/KEAP1 triple mutant LUAD. ConclusionsWe identify SMARCA4/STK11/KEAP1 triple mutant LUAD as a prognostically significant disease subset and nominate TGF-{beta} signaling as a potential therapeutic target.
Full-text reasoning
From the deep-tier full-text analysis of this preprint.
Reasoning review — 6 key claims, 3 well-supported, 3 with gaps
- partial SMARCA4/STK11/KEAP1 triple mutant LUAD is associated with poor survival and high frequency of multisite metastasis. gap: The authors acknowledge that clinical sample availability for triple mutants is statistically limited, weakening the robustness of this specific clinical association.
- partial SMARCA4/STK11/KEAP1 triple mutant LUAD is a prognostically significant disease subset. gap: This conclusion relies on clinical data which the authors themselves state is statistically limited due to low sample availability.
- supported SMARCA4/STK11/KEAP1 triple knockout models show enhanced migration, invasion, and diversified organotropism.
- supported SMARCA4/STK11/KEAP1 triple mutant LUAD (clinical/models) shows upregulation of TGF-β signaling and EMT gene signatures.
- supported SMARCA4/STK11/KEAP1 triple mutant LUAD (clinical/models) shows corresponding changes in chromatin accessibility.
- unsupported TGF-β signaling is a potential therapeutic target for SMARCA4/STK11/KEAP1 triple mutant LUAD. gap: The results section does not present any evidence from the 'interrogated functional dependency' to support that TGF-β signaling is a functional dependency or a therapeutic target, only that it is upregulated.
Claims and gaps are read from the full text by a language model, shown for transparency; they do not affect ranking or selection.
Lifecycle
- biorxiv v1 2026-06-08 source ↗
Discussion
No qualifying discussion yet.