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Review Article | Open Access

Insights into targeting LKB1 in tumorigenesis

Charles B. Trelforda,b( )Trevor G. Shepherda,b,c,d
The Mary & John Knight Translational Ovarian Cancer Research Unit, London Regional Cancer Program, London, ON N6A 4L6, Canada
Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
Department of Oncology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
Department of Obstetrics and Gynaecology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada

Peer review under the responsibility of the Genes & Diseases Editorial Office, in alliance with the Association of Chinese Americans in Cancer Research (ACACR, Baltimore, MD, USA).

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Abstract

Genetic alterations to serine-threonine kinase 11 (STK11) have been implicated in Peutz-Jeghers syndrome and tumorigenesis. Further exploration of the context-specific roles of liver kinase B1 (LKB1; encoded by STK11) observed that it regulates AMP-activated protein kinase (AMPK) and AMPK-related kinases. Given that both migration and proliferation are enhanced with the loss of LKB1 activity combined with the prevalence of STK11 genetic alterations in cancer biopsies, LKB1 was marked as a tumor suppressor. However, the role of LKB1 in tumorigenesis is paradoxical as LKB1 activates autophagy and reactive oxygen species scavenging while dampening anoikis, which contribute to cancer cell survival. Due to the pro-tumorigenic properties of LKB1, targeting LKB1 pathways is now relevant for cancer treatment. With the recent successes of targeting LKB1 signaling in research and clinical settings, and enhanced cytotoxicity of chemical compounds in LKB1-deficient tumors, there is now a need for LKB1 inhibitors. However, validating LKB1 inhibitors is challenging as LKB1 adaptor proteins, nucleocytoplasmic shuttling, and splice variants all manipulate LKB1 activity. Furthermore, STE-20-related kinase adaptor protein (STRAD) and mouse protein 25 dictate LKB1 cellular localization and kinase activity. For these reasons, prior to assessing the efficacy and potency of pharmacological candidates, the functional status of LKB1 needs to be defined. Therefore, to improve the understanding of LKB1 in physiology and oncology, this review highlights the role of LKB1 in tumorigenesis and addresses the therapeutic relevancy of LKB1 inhibitors.

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Genes & Diseases
Article number: 101402
Cite this article:
Trelford CB, Shepherd TG. Insights into targeting LKB1 in tumorigenesis. Genes & Diseases, 2025, 12(2): 101402. https://doi.org/10.1016/j.gendis.2024.101402

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Received: 14 February 2024
Revised: 03 June 2024
Accepted: 22 June 2024
Published: 28 August 2024
© 2024 The Authors.

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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