Tumor-agnostic therapy: a potential therapeutic approach for SMARCA4-deficient malignancies

SMARCA4 deficiency plays a critical role in the oncogenesis of various aggressive tumors that exhibit resistance to conventional chemotherapy and radiotherapy, posing significant challenges to clinical management. The pivotal role of SMARCA4 deficiency in tumorigenesis suggests the need for a paradigm shift from traditional tumor origin-based approaches to novel tumor-agnostic strategies focused on molecular alterations associated with SMARCA4 deficiency. This review explores potential targetable molecular changes and emerging therapeutic strategies for SMARCA4-deficient tumors. Molecular alterations related to SMARCA4 deficiency involve impaired genomic stability, defects in DNA mismatch repair, and elevated tumor mutation burdens, all of which suggest potential sensitivity to immune checkpoint inhibitors (ICIs). Recent studies indicate that combining ICIs with chemotherapy or anti-angiogenic agents as first-line treatments may offer clinical benefits for SMARCA4-deficient tumors. Furthermore, SMARCA4 deficiency epigenetically affects chromatin accessibility, alters the distribution of Polycomb group proteins on chromatin, and modulates histone acetylation, highlighting the potential efficacy of epigenetic regulators such as EZH2 and HDAC inhibitors. In addition, synthetic lethality strategies targeting vulnerabilities in SMARCA4-deficient tumors are promising therapeutic approaches, including inhibitors of SMARCA2, CDK4/6, ATR, CHK1, PARP, and the oxidative phosphorylation pathway. Based on current clinical evidence, ICI-based combination therapies represent the most promising first-line regimens for SMARCA4-deficient tumors. Although a theoretical basis supports the potential of tumor-agnostic therapy as a promising strategy for these tumors, several challenges remain in clinical practice. These include heterogeneous therapeutic responses across tumor types, safety concerns associated with synthetic lethality-based agents, and the absence of any histology-agnostic approved therapy for SMARCA4-deficient tumors. The continued development of novel therapeutics and further large-scale clinical evaluations are essential to overcoming these barriers.