Abstract
The overall survival of lung cancer patients remains dismal despite the availability of targeted therapies. Oncofetal protein SALL4 is a novel cancer target. We herein report that SALL4 was aberrantly expressed in a subset of lung cancer patients with poor survival. SALL4 silencing by RNA interference or SALL4 peptide inhibitor treatment led to impaired lung cancer cell growth. Expression profiling of SALL4-knockdown cells demonstrated that both the EGFR and IGF1R signaling pathways were affected. Connectivity Map analysis revealed the HDAC inhibitor entinostat as a potential drug in treating SALL4-expressing cancers, and this was confirmed in 17 lung cancer cell lines. In summary, we report for the first time that entinostat can target SALL4-positive lung cancer. This lays the foundation for future clinical studies evaluating the therapeutic efficacy of entinostat in SALL4-positive lung cancer patients.
Highlights
Lung cancer is the leading cause of cancer deaths in both men and women in the United States and worldwide
To determine whether SALL4 is aberrantly expressed in lung cancer, we performed immunohistochemistry (IHC) to analyze the protein expression level of SALL4 in a cohort of lung cancer patients from the archives of the National University Hospital, Singapore, with normal lung tissues serving as control
Within the non-small cell lung cancers (NSCLCs) cases, SALL4 was found to be positive in 12% of adenocarcinomas (ADC) (n=100), 19% of adenocarcinoma in situ (n=21) and 23% of squamous cell carcinoma (SCC) (n=52)
Summary
Lung cancer is the leading cause of cancer deaths in both men and women in the United States and worldwide. It can be divided into small cell lung cancer (~20%) and non-small cell lung cancer (NSCLC, ~80%)[1]. Major treatment options for NSCLC, depending on the stages of disease, include surgery, radiation, and platinum doublet chemotherapy. While other driver mutations, including HER2, MET, NRAS, BRAF, FGFR1, PIK3CA, AKT1, RET, and ROS1 may represent viable therapeutic targets, overall they occur only at low frequency in NSCLC, with more than 50% of cases still lacking defined driver mutation [5,6,7,8,9]. Therapeutic options are still limited for many advanced NSCLC patients. Acquired resistance to the existing targeted agents and disease recurrence present further challenges and highlight the urgent need for alternative treatment strategies [10, 11]
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