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

Yifan Kong, Derek B. Allison, Qiongsi Zhang, Daheng He, Yuntong Li, Fengyi Mao, Chaohao Li, Zhiguo Li, Yanquan Zhang, Jianlin Wang, Chi Wang, Christine F. Brainson, Xiaoqi Liu

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article numbereabj4009
JournalScience Signaling
Volume15
Issue number754
DOIs
StatePublished - Oct 4 2022

Bibliographical note

Funding Information:
We thank G. de Cárcer (Spanish National Cancer Research Centre) and A. Kasinski (Purdue University) for providing the transgenic mice. This work was supported by NIH R01 CA157429 (to X.L.), R01 CA196634 (to X.L.), R01 CA264652 (to X.L.), and R01 CA256893 (to X.L.). This research was also supported by the Biospecimen Procurement and Translational Pathology, Biostatistics and Bioinformatics, Flow Cytometry and Immune Monitoring Shared Resources of the University of Kentucky Markey Cancer Center (P30CA177558).

Publisher Copyright:
Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S.

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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