Abstract Lung adenocarcinoma (LUAD), the most common subtype of non-small cell lung cancer (NSCLC), frequently relies on epigenetic plasticity to support growth, stress adaptation, and therapeutic escape. Among the chromatin mechanisms enabling this plasticity, histone variant exchange is central. Incorporation of specific variants reshapes DNA accessibility and transcriptional programs, underpinning cancer cell adaptability. VPS72, a histone chaperone shared by the SRCAP and TIP60 complexes, mediates ATP-dependent deposition of the H2A.Z-H2B dimer into regulatory chromatin, thereby promoting proliferation, lineage state, immune evasion, and treatment tolerance transcriptional programs. H2A.Z deposition is linked to aggressive malignancy; however, the contribution of VPS72 itself to LUAD progression remains undefined. Given its central role in H2A.Z loading, the VPS72-H2A.Z axis may represent a key epigenetic driver and potentially targetable vulnerability. TCGA LUAD datasets were analyzed to profile VPS72 expression, genomic correlates, and functional relevance. VPS72 was significantly upregulated relative to normal tissue and associated with greater genomic instability, higher tumor mutational burden, stronger hypoxia signatures, earlier clinical detectability, and reduced overall survival. High VPS72 expression was also observed in female patients and ever-smokers, indicating exposure-linked modulation. Functional evaluation in LUAD models showed that genome-wide CRISPR and RNAi screens identified VPS72 as a major fitness gene. shRNA-mediated VPS72 depletion reduced proliferation and Ki-67 expression, reduced colony formation, impaired migration and invasion, and abrogated anchorage-independent growth. Transcriptional profiling revealed that VPS72 loss strongly repressed MYC- and E2F-driven cell-cycle programs and disrupted metabolic pathways, including heme biosynthesis, mitochondrial respiration, calcium signaling, and hypoxia adaptation. Although H2A.Z itself is not directly targetable, VPS72 role in its deposition creates a druggable interface. To exploit this, we developed cell-permeable peptides that block the VPS72-H2A.Z interaction, which phenocopied VPS72 knockdown by inducing apoptosis and suppressing LUAD cell growth in a dose-dependent manner. Collectively, these findings identify VPS72 as a central epigenetic regulator and therapeutically actionable vulnerability in LUAD. Disrupting the VPS72-H2A.Z axis attenuates oncogenic transcriptional programs and malignant behaviors, offering a promising strategy to overcome epigenetic plasticity and treatment resistance in aggressive NSCLC. Citation Format: Xzaviar Kaymar Solone, Selim Reza, Kalpana Subedi, Nirmal Parajuli, Li Zhou, Qing-Sheng Mi. The VPS72-H2A.Z-axis is an underappreciated oncogenic vulnerability in lung adenocarcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1926.
Solone et al. (Fri,) studied this question.