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Targeting LKB1 in cancer - exposing and exploiting vulnerabilities - PubMed

  • ️Thu Jan 01 2015

Review

. 2015 Aug 11;113(4):574-84.

doi: 10.1038/bjc.2015.261. Epub 2015 Jul 21.

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Review

Targeting LKB1 in cancer - exposing and exploiting vulnerabilities

M Momcilovic et al. Br J Cancer. 2015.

Abstract

The LKB1 tumour suppressor is a serine/threonine kinase that functions as master regulator of cell growth, metabolism, survival and polarity. LKB1 is frequently mutated in human cancers and research spanning the last two decades have begun decoding the cellular pathways deregulated following LKB1 inactivation. This work has led to the identification of vulnerabilities present in LKB1-deficient tumour cells. Pre-clinical studies have now identified therapeutic strategies targeting this subset of tumours that promise to benefit this large patient population harbouring LKB1 mutations. Here, we review the current efforts that are underway to translate pre-clinical discovery of therapeutic strategies targeting LKB1 mutant cancers into clinical practice.

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Figures

Figure 1
Figure 1

LKB1 regulates an AMPK-like family of kinase. LKB1 in complex with STRAD and MO25 phosphorylates AMPK and AMPK-like kinases to regulate polarity, adhesion, growth, metabolism and cell survival.

Figure 2
Figure 2

LKB1-deficient cells show select sensitivity to energetic stress. In the presence of energetic stress, LKB1-competent cells activate AMPK, which results in growth restriction and cell survival. LKB1-deficient cells in the presence of energetic stress fail to activate AMPK and thus continue with unrestricted growth leading to metabolic catastrophe and cell death.

Figure 3
Figure 3

LKB1 regulation of AMPK and MARK signalling pathways. Phosphorylation of AMPK leads to phosphorylation of ULK1/2 and Raptor. As a result of phosphorylation of ULK1/2, autophagy and mitophagy are upregulated. Phosphorylation of Raptor by AMPK leads to downregulation of mTOR activity and its downstream targets S6 and 4E-BP1. LKB1 phosphorylates MARK1/4 leading to phosphorylation of DIXDC1 and inhibition of SNAIL protein through regulation of FAK and SRC kinases controlling both cell adhesion and migration.

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