The kinase PLK1 promotes the development of Kras/Tp53-mutant lung adenocarcinoma through transcriptional activation of the receptor RET
Menée à l'aide de modèles murins d'une forme commune d'adénocarcinome pulmonaire humain, cette étude met en évidence un mécanisme par lequel un niveau d'expression élevé de la kinase PLK1 favorise, via l'activation transcriptionnelle du récepteur RET, le développement de tumeurs avec mutations KRAS/TP53
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 KRASG12D-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. The kinase PLK1 fuels lung cancer growth by amplifying tumorigenic MAPK signaling. The kinase PLK1 mediates the process of cell division, which drives the growth of many cancers. Using genetically modified mouse models of a common form of human lung adenocarcinoma in which PLK1 abundance is increased, Kong et al. identified an independent mechanism through which PLK1 fueled tumor growth. In Kras-mutant murine lung adenocarcinoma cells in culture and in mice, PLK1 kinase activity resulted in increased expression of the gene encoding the receptor kinase RET. Together with KRAS, RET activated the mitogen-activated protein kinase (MAPK) pathway, which promotes tumor growth. Combining the MAPK pathway inhibitor trametinib with the RET inhibitor pralsetinib (both of which are clinically approved for some lung cancers) induced tumor regression and prolonged survival in a mouse model of lung cancer with high PLK1 abundance. The findings suggest a potential therapeutic strategy for some lung adenocarcinomas.
Science Signaling 2022