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Published on: March 30, 2019
Multi-omics integrative analysis elucidates the molecular characteristics of SMARCA4-deficient lung adenocarcinoma
Deyu Guo1, Kai Wang2, Shijie Sun3
1Institute of Oncology, Shandong Provincial Hospital, Shandong University, Jinan, China.
Abstract:
SMARCA4-deficient lung adenocarcinoma (LUAD) is highly aggressive with multiple oncogene mutations, and has low sensitivity to chemotherapy, targeted therapy and immunotherapy. By integrating multi-omics analysis and machine learning analysis on 20 lung adenocarcinoma datasets, we characterized SMARCA4 mutation in clinical prognosis, metabolic level, immune infiltration and pathway enrichment. The key role of SMARCA4 in LUAD development was confirmed by several in vitro and in vivo experiments. SMARCA4 is highly expressed in LUAD tissues compared with adjacent tissues, and SMARCA4 mutation is a poor prognostic factor. Although SMARCA4-deficient LUAD patients are not sensitive to common chemotherapeutic drugs, immunotherapy is an alternative treatment for lung adenocarcinoma. SMARCA4 deletion is associated with a high rate of oncogene co-mutation. Co-mutation of KRAS was found to have a significant impact on the response to multiple types of chemotherapy. Unique metabolic profiles, abnormal cell cycle and hyperactivation of oxidative phosphorylation were hallmarks of SMARCA4 mutant LUAD. We screened four chemotherapeutic agents targeting MTOR pathway, oxidative stress, DNA replication or cell cycle, including rapamycin and ribociclib, as potential chemotherapeutic agents for SMARCA4-deficient lung adenocarcinoma. In vitro assays showed that SMARCA4 knockdown significantly inhibited DNA replication, cell cycle and cell proliferation in lung adenocarcinoma cells, and significantly promoted oxidative stress and apoptosis in lung adenocarcinoma cells. Our comprehensive findings advance our understanding of SMARCA4 mutant LUAD gene mutation and immune microenvironment, providing insights into potential therapeutic approaches and research directions for SMARCA4-deficient LUAD.
Insights
SMARCA4-deficient lung adenocarcinoma (LUAD) is aggressive and treatment-resistant. This study reveals unique metabolic and immune profiles, identifying potential therapeutic targets like MTOR pathway inhibitors for this challenging cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- SMARCA4-deficient lung adenocarcinoma (LUAD) presents as a highly aggressive malignancy.
- It exhibits limited sensitivity to conventional chemotherapy, targeted therapies, and immunotherapy.
- Understanding its unique biological characteristics is crucial for developing effective treatments.
Purpose of the Study:
- To comprehensively characterize SMARCA4 mutations in LUAD.
- To investigate the clinical, metabolic, immune, and pathway enrichment aspects of SMARCA4-deficient LUAD.
- To identify potential therapeutic strategies for SMARCA4-deficient LUAD.
Main Methods:
- Integrated multi-omics and machine learning analyses on 20 LUAD datasets.
- In vitro and in vivo experiments to validate the role of SMARCA4.
- Screening of chemotherapeutic agents targeting specific pathways.
Main Results:
- SMARCA4 mutation is a poor prognostic factor in LUAD, associated with high oncogene co-mutation rates (e.g., KRAS).
- SMARCA4-deficient LUAD exhibits distinct metabolic profiles, including abnormal cell cycle and hyperactivated oxidative phosphorylation.
- Rapamycin and ribociclib were identified as potential therapeutic agents, with SMARCA4 knockdown inhibiting proliferation and promoting apoptosis.
Conclusions:
- SMARCA4 plays a critical role in LUAD development and progression.
- Targeting metabolic pathways and cell cycle regulation offers promising therapeutic avenues for SMARCA4-deficient LUAD.
- Further research into the immune microenvironment and therapeutic strategies for SMARCA4-deficient LUAD is warranted.
