The kinase PLK1 promotes the development of Kras / Tp53 -mutant lung adenocarcinoma through transcriptional activation of the receptor RET

• Published in: Science signaling 2022-10, Vol.15 (754), p.eabj4009-eabj4009
• Main Authors: Kong, Yifan, Allison, Derek B, Zhang, Qiongsi, He, Daheng, Li, Yuntong, Mao, Fengyi, Li, Chaohao, Li, Zhiguo, Zhang, Yanquan, Wang, Jianlin, Wang, Chi, Brainson, Christine F, Liu, Xiaoqi
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Adenocarcinoma of Lung - genetics; Animal models; Animals; Cell culture; Cell Cycle Proteins - metabolism; Cell division; Cell Line, Tumor; Gene expression; Genetic modification; Humans; K-Ras protein; Kinases; Lung cancer; Lung Neoplasms - metabolism; MAP kinase; Mice; Mitogen-Activated Protein Kinase Kinases - genetics; Mitogen-Activated Protein Kinases - metabolism; Mitosis; Mutants; p53 Protein; Polo-Like Kinase 1; Protein kinase; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-ret - genetics; Proto-Oncogene Proteins c-ret - metabolism; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; Receptors; Transcription activation; Transcription Factors - metabolism; Transcriptional Activation; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors; Tyrosine kinase inhibitors
• ISSN: 1945-0877; 1937-9145
• DOI: 10.1126/scisignal.abj4009

Increased abundance of polo-like kinase 1 (PLK1) is observed in various tumor types, particularly in lung adenocarcinoma (LUAD). Here, we found that PLK1 accelerated the progression of LUAD through a mechanism that was independent of its role in mediating mitotic cell division. Analysis of human tumor databases revealed that increased PLK1 abundance in LUAD correlated with mutations in KRAS and p53, with tumor stage, and with reduced survival in patients. In a mouse model of KRAS -driven, p53-deficient LUAD, PLK1 overexpression increased tumor burden, decreased tumor cell differentiation, and reduced animal survival. PLK1 overexpression in cultured cells and mice indirectly increased the expression of the gene encoding the receptor tyrosine kinase RET by phosphorylating the transcription factor TTF-1. Signaling by RET and mutant KRAS in these tumors converged to activate the mitogen-activated protein kinase (MAPK) pathway. Pharmacological inhibition of the MAPK pathway kinase MEK combined with inhibition of either RET or PLK1 markedly suppressed tumor growth. Our findings show that PLK1 can amplify MAPK signaling and reveal a potential target for stemming progression in lung cancers with high PLK1 abundance.