ARID1A mutational status in non-small cell lung cancer: from molecular pathology to clinical implications with a focus on the relationships with EGFR.

Lung cancer is the most frequently diagnosed malignancy worldwide and remains the leading cause of cancer-related mortality. Non-small-cell lung cancer (NSCLC) is the most prevalent type of lung cancer, with epidermal growth factor receptor (EGFR) gene mutations being among the most frequently reported. ARID1A (AT-Rich Interactive Domain 1A), a key component of the switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex, has emerged as a tumor suppressor in multiple cancers and is mutated in approximately 8 % of lung cancers, primarily as a loss-of-function (LOF) alteration, which allows the gene to be considered a potential molecular marker, predictive of poor NSCLC prognosis. Co-occurrence of ARID1A LOF mutations and EGFR alterations presents complex biological and therapeutic challenges. ARID1A LOF mutations negatively affect the efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs) via several molecular mechanisms, including the aberrant activation of the phosphoinositide 3-kinase/serine-threonine kinase (PI3K/AKT) signaling pathway. This leads to decreased apoptosis, increased tumor angiogenesis, enhanced proliferation, and greater metastatic potential. On the other hand, ARID1A LOF mutations have emerged as promising predictive biomarkers for favorable responses to immune checkpoint inhibitors (ICIs). The underlying mechanisms include modulation of epithelial-to-mesenchymal transition (EMT), alterations in the tumor immune microenvironment (TIME), impaired mismatch repair (MMR) function, increased tumor mutation burden (TMB), enhanced neoantigen presentation, and upregulation of programmed death ligand 1 (PD-L1) and type I interferon (IFN-I) expression. These findings highlight the dual role of ARID1A mutations as prognostic and predictive biomarkers, underscoring the need for further investigation into their complex biological and therapeutic implications.