Targeting hyperactive TGFBR2 for treating MYOCD deficient lung cancer
Qian Zhou1, Wensheng Chen1, Zhenzhen Fan1
1MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.
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.
Insights
Loss of the tumor suppressor gene MYOCD in lung cancer promotes stemness and drug resistance. MYOCD-deficient lung cancers are sensitive to TGFBR kinase inhibitors, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Drug resistance limits cancer therapy success, often due to tumor suppressor gene (TSG) loss.
- Developing strategies for resistant tumors is a critical clinical need.
Purpose of the Study:
- To investigate the role of MYOCD as a tumor suppressor gene in lung cancer.
- To explore MYOCD's function in regulating lung cancer stem cells and its therapeutic implications.
Main Methods:
- In vitro and in vivo experiments to confirm MYOCD's tumor suppressive function.
- Analysis of MYOCD's mechanism in inhibiting lung cancer stemness.
- Investigating MYOCD's interaction with the TGFBR2 promoter and epigenetic silencing complex.
Main Results:
- MYOCD demonstrates potent inhibition of lung cancer stem cell stemness.
- MYOCD recruits the PRMT5/MEP50 complex to epigenetically silence TGFBR2.
- Non-small cell lung cancer (NSCLC) cells lacking MYOCD show heightened sensitivity to TGFBR kinase inhibitors (TGFBRi).
Conclusions:
- Loss of MYOCD function creates a vulnerability in lung cancer cells.
- TGFBRi can be a targeted therapy for MYOCD-deficient lung cancers.
- Combination therapies involving TGFBRi and stemness inhibitors show promise for treating MYOCD-deficient lung cancers.
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