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.
Highlights
Liver kinase B1 (LKB1, known as STK11) was first identified as the causal mutation in Peutz–Jeghers Syndrome (PJS), a rare inherited autosomal dominant disorder characterised by the development of benign gastrointestinal hamartomas and the early onset of cancer (Hemminki et al, 1998)
LKB1 is a serine threonine kinase that directly phosphorylates and regulates the adenosine monophosphateactivated protein kinase (AMPK) and 12 other AMPK-like kinases to regulate a broad spectrum of cellular functions including: growth, metabolism, autophagy and polarity (Figure 1) (Shackelford and Shaw, 2009)
Selective killing of LKB1-deficient tumour cells can be achieved by mimicking energy stress with small molecule AMPK agonists such as the AMP mimetic AICAR or the biguanide metformin and phenformin, which are both inhibitors of mitochondrial complex I (Dykens et al, 2008) (Table 1)
Summary
It will be critical to implement standardised genetic and molecular screening of LKB1 inactivation for patients. Functional assays that directly measure the LKB1 activation following treatment with AMPK activators such as AICAR or phenformin could in theory be performed on tumour biopsies cultured ex vivo (Shaw et al, 2004b; Hawley et al, 2010). This type of assay would require culturing and/or preserving tumour biopsies ex vivo and could serve as a simple and routine screening method to detect LKB1 deficiencies. Tumour cells lacking LKB1 are hypersensitive to apoptosis in culture following treatment with energy stress-inducing agents, presumably originating from an inability to restore ATP levels owing to AMPK deficiency (Shaw et al, 2004b). Multi-target receptor tyrosine kinases ER, glycolysis, unfolded protein response Lysyl oxidase
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