LKB1 Tumor Suppressor: Therapeutic Opportunities Knock when LKB1 Is Inactivated

Abstract

LKB1 is commonly thought of as a tumor suppressor gene because its hereditary mutation is responsible for a cancer syndrome, and somatic inactivation of LKB1 is found in non-small cell lung cancer, melanoma, and cervical cancers. However, unlike other tumor suppressors whose main function is to either suppress cell proliferation or promote cell death, one of the functions of LKB1-regulated AMPK signaling is to suppress cell proliferation in order to promote cell survival under energetic stress conditions. This unique, pro-survival function of LKB1 has led to the discovery of reagents, such as phenformin, that specifically exploit the vulnerability of LKB1-null cells in their defect in sensing energetic stress. Such targeted agents represent a novel treatment strategy because they induce cell killing when LKB1 is absent. This review article summarizes various vulnerabilities of LKB1-mutant cells that have been reported in the literature and discusses the potential of using existing or developing novel reagents to target cancer cells with defective LKB1.

Keywords: Tumor Suppressor; metabolic stress; targeted therapy; tumor vulnerability.

Figure 1

The effects of AMPK activators in LKB1-wild type and mutant cells. Metformin and phenformin inhibit mitochondria complex I, which results in the depletion of intracellular ATP and increases in AMP. The binding of AMP to the AMPK activates AMPK kinase activity and its metabolic regulation function. The lack of LKB1 prevents the activation of AMPK by AMP. As a result, metformin and phenformin induced energetic stress cannot be properly detected in LKB1-mutant cells, which eventually lead to cell death.

Figure 2

AMPK regulates protein translation through its effects on mTOR and pre-rRNA synthesis. The activation of AMPK suppresses mTOR activity, thus interfering with translation initiation. AMPK also phosphorylates TIF-IA to prevent the assembly of pre-rRNA transcription initiation complex, thus prevent the synthesis of ribosome which is required for protein translation.

Figure 3

The role of LKB1 as a ROS sensor but not a genomic stress sensor. Ionization radiation activates ATM and AMPK in a LKB1-independent manner to sense genomic stress. LKB1/AMPK is required for reactive oxygen species (ROS) to activate mTOR through cytosolic ATM.

Figure 4

LKB1 negatively regulates YAP1 function. LKB1 regulates SCRIB cellular localization through its phosphorylation of MARK. The proper cellular localization of SCRIB is required for the regulation of YAP phosphorylation by its upstream kinases, such as MST and LATS.