Targeting Mediator MED23 in Ras-Active Lung Caner

Lung cancer is the leading cause of cancer-related mortality worldwide. A point mutation in the K-Ras gene and aberrant Ras–MAPK signaling often contribute to the malignant phenotype of lung cancer. However, efforts to develop Ras-directed therapies are challenged by the difficulty in selectively targeting the activated Ras GTPase. Now researchers from Chinese Academy of Sciences demonstrates that through sensing the signal strength of Ras/MAPK pathway, Mediator MED23 and its binding transcription factor ELK1, are selectively required for the Ras-driven oncogenesis.

 

Mediator subunit MED23 (Sur2) was identified originally as a genetic regulator of hyperactive Ras in C. elegans. The loss of Med23 could suppress the abnormal vulval growth, a phenotype resulted from activated Ras. In the current study, Dr. WANG Gang’s group from Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences observed that Mediator MED23 and its interacting transcription factor ELK1 specifically control the proliferation and tumorigenesis of the Ras-active lung cancer cells and the process of Ras-transfomation. Gene profiling revealed that MED23 and ELK1 co-regulate a set of cell cycle/proliferation genes. Correlated with high-level ELK1 phosphorylation, MED23 is overexpressed in lung cancer cell lines and clinical lung cancer samples with active Ras activities. Significantly, lower Med23 expression can predict better survival in Ras-active lung cancer patients and xenograft mice.

 

In summary, cancer cells harboring K-Ras mutations are not only addicted to oncogenic K-Ras but also rely on the entire Ras/MAPK pathway, including the downstream cofactor MED23 and ELK1, to maintain the addiction. Thus, MED23, ELK1, or their interaction interface may represent multiple pharmaceutical targets in patients with Ras-mutated lung cancer, for whom currently there is no effective therapy.

 

This study was recently published online in the Proceedings of the National Academy of Sciences of the United States of America, and it was supported in part by grants from the Ministry of Science and Technology of China, Chinese Academy of Sciences and the National Natural Science Foundation of China.

 

CONTACT:

WANG Gang

Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China

Email: gwang22@sibs.ac.cn; Tel: 86-21-54921083

 

A Schematic model for “Oncogenic Pathway Addiction”: after the progressive accumulation of mutations, such as oncogenic Ras mutations, the entire Ras/MAPK pathway could become hyperactive, resulting in activation of ELK1 and up-regulated MED23. Therefore, cancer cells with Ras mutations become heavily dependent on the Ras/MAPK/ELK1/MED23 pathway for the maintenance of the malignant phenotype. Targeting MED23, ELK1, or their interaction may counteract the oncogenic signaling transduction in the Ras-driven cancer cells (Image provided by Dr. WANG Gang).