Targeting hyperactive TGFBR2 for treating MYOCD deficient lung cancer.

Abstract

Purpose: Clinical success of cancer therapy is severely limited by drug resistance, attributed in large part to the loss of function of tumor suppressor genes (TSGs). Developing effective strategies to treat those tumors is challenging, but urgently needed in clinic. Experimental Design: MYOCD is a clinically relevant TSG in lung cancer patients. Our in vitro and in vivo data confirm its tumor suppressive function. Further analysis reveals that MYOCD potently inhibits stemness of lung cancer stem cells. Mechanistically, MYOCD localizes to TGFBR2 promoter region and thereby recruits PRMT5/MEP50 complex to epigenetically silence its transcription. Conclusions: NSCLC cells deficient of MYOCD are particularly sensitive to TGFBR kinase inhibitor (TGFBRi). TGFBRi and stemness inhibitor synergize with existing drugs to treat MYOCD deficient lung cancers. Our current work shows that loss of function of MYOCD creates Achilles' heels in lung cancer cells, which might be exploited in clinic.

• Authors: Qian Zhou, Wensheng Chen, Zhenzhen Fan, Zhipeng Chen, Jinxia Liang, Guandi Zeng, Lu Liu, Wanting Liu, Tong Yang, Xin Cao, Biao Yu, Meng Xu, Ye-Guang Chen, Liang Chen
• Journal: Theranostics (Theranostics) Vol. 11 Issue 13 Pg. 6592-6606 ( 2021) ISSN: 1838-7640 [Electronic] Australia
• PMID: 33995678 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The author(s).

Chemical References

• Adaptor Proteins, Signal Transducing
• Antineoplastic Agents
• MEP50 protein, human
• Neoplasm Proteins
• Nuclear Proteins
• Protein Kinase Inhibitors
• Trans-Activators
• myocardin
• PRMT5 protein, human
• Protein-Arginine N-Methyltransferases
• Receptor, Transforming Growth Factor-beta Type II
• TGFBR2 protein, human

Topics

• Adaptor Proteins, Signal Transducing (physiology)
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics)
• Down-Regulation
• Drug Synergism
• Gene Expression Regulation, Neoplastic
• Gene Silencing
• Histone Code
• Humans
• Lung Neoplasms (drug therapy, genetics)
• Methylation
• Mice, Transgenic
• Neoplasm Proteins (antagonists & inhibitors, biosynthesis, genetics, physiology)
• Neoplastic Stem Cells (pathology)
• Nuclear Proteins (biosynthesis, deficiency, genetics, physiology)
• Promoter Regions, Genetic
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Protein Processing, Post-Translational
• Protein-Arginine N-Methyltransferases (physiology)
• Receptor, Transforming Growth Factor-beta Type II (antagonists & inhibitors, genetics)
• Signal Transduction
• Trans-Activators (biosynthesis, deficiency, genetics, physiology)
• Tumor Burden