LKB1/KRAS mutant lung cancers constitute a genetic subset of NSCLC with increased sensitivity to MAPK and mTOR signalling inhibition

Mahoney, Claire; Choudhury, Bhudipa; Davies, Helen; Edkins, Sarah; Greenman, Chris; Haaften, Gijs van; Mironenko, Tatiana; Santarius, Thomas; Stevens, C; Stratton, Michael R.; Futreal, P. Andrew

doi:10.1038/sj.bjc.6604886

Cited by 113 publications

(95 citation statements)

References 22 publications

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“…Once the LKB1 gene is mutated, metformin may only inhibit proliferation by downregulating MAPK. These observations are consistent with previous studies (31)(32)(33).…”

Section: Discussionsupporting

confidence: 94%

K-ras gene mutation as a predictor of cancer cell responsiveness to metformin

Guo

Wang

et al. 2013

Molecular Medicine Reports

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Abstract. An increasing number of studies support the use of metformin, a common antidiabetic drug, as a novel anticancer therapeutic. However, its mechanism of action has yet to be identified. In the current study, metformin was observed to effectively inhibit the growth of the K-ras mutant but not wild-type tumors in vivo. The antitumor effects of metformin were mediated by the induction of apoptosis and inhibition of proliferation in vivo. In addition, metformin induced apoptosis in the K-ras mutant tumors, A549 and PANC-1, but not in the K-ras wild-type tumor, A431, in vitro. Similarly, at lower concentrations, metformin inhibited cell proliferation in the K-ras mutant, but not in the K-ras wild-type tumor cells in vitro. These observations indicate that tumors with K-ras mutations are sensitive to metformin therapy. In addition, metformin significantly arrested K-ras mutant and wild-type tumor cells in G1 phase in vitro and metformin downregulated two important downstream effectors of the Ras signaling pathway in K-ras mutant tumors. Metformin was concluded to function as a potential K-ras-targeting agent that has potential for cancer therapy.

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“…Once the LKB1 gene is mutated, metformin may only inhibit proliferation by downregulating MAPK. These observations are consistent with previous studies (31)(32)(33).…”

Section: Discussionsupporting

confidence: 94%

K-ras gene mutation as a predictor of cancer cell responsiveness to metformin

Guo

Wang

et al. 2013

Molecular Medicine Reports

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“…Coexisting STK11/LKB1 and KRAS mutations sensitize NSCLC cells to either mTOR or MEK inhibition (18), and evidence from xenograft experiments also supports the use of dual PI3K/mTOR inhibition in this context (4). Mouse models have demonstrated that LKB1 loss can also cooperate with PTEN loss to drive the tumorigenesis of a (19).…”

Section: Tumors With Stk11/lkb1 Alterationsmentioning

confidence: 88%

“…Nearly one-third of NSCLC samples harbor inactivating alterations of STK11/LKB1 (16), which are known to frequently coexist with KRAS mutations, and are thought to play an important role in progression to metastasis (17,18). Coexisting STK11/LKB1 and KRAS mutations sensitize NSCLC cells to either mTOR or MEK inhibition (18), and evidence from xenograft experiments also supports the use of dual PI3K/mTOR inhibition in this context (4).…”

Section: Tumors With Stk11/lkb1 Alterationsmentioning

confidence: 99%

Picking the Point of Inhibition: A Comparative Review of PI3K/AKT/mTOR Pathway Inhibitors

Dienstmann¹,

Rodón²,

Serra³

et al. 2014

Molecular Cancer Therapeutics

395

331

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The frequent activation of the PI3K/AKT/mTOR pathway in cancer, and its crucial role in cell growth and survival, has made it a much desired target for pharmacologic intervention. Following the regulatory approval of the rapamycin analogs everolimus and temsirolimus, recent years have seen an explosion in the number of phosphoinositide 3-kinase (PI3K) pathway inhibitors under clinical investigation. These include: ATPcompetitive, dual inhibitors of class I PI3K and mTORC1/2; "pan-PI3K" inhibitors, which inhibit all four isoforms of class I PI3K (a, b, d, g); isoform-specific inhibitors of the various PI3K isoforms; allosteric and catalytic inhibitors of AKT; and ATP-competitive inhibitors of mTOR only (and thus mTORC1 and mTORC2). With so many agents in development, clinicians are currently faced with a wide array of clinical trials investigating a multitude of inhibitors with different mechanisms of action, being used both as single agents and in combination with other therapies. Here, we provide a review of the literature, with the aim of differentiating the genomic contexts in which these various types of inhibitors may potentially have superior activity.

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“…LKB1 was first recognized as a tumor-suppressor gene because its mutations cause Peutz-Jeghers syndrome, characterized by gastrointestinal hamartoma with an increased cancer risk (Giardiello et al, 2000;van Lier et al, 2010). This gene was later found to be a target for mutational inactivation in human malignancies including non-small cell lung carcinoma (Sanchez-Cespedes et al, 2002;Carretero et al, 2004;Ji et al, 2007;Matsumoto et al, 2007;Makowski and Hayes, 2008;Komiya et al, 2010;Mahoney et al, 2009), cervical carcinoma (Wingo et al, 2009), melanoma (Guldberg et al, 1999;Rowan et al, 1999) and others (Sanchez-Cespedes, 2007). The LKB1 gene encodes a serine/threonine kinase essential for the activation of AMPK (AMP-activated protein kinase) and 12 AMPK-related kinases; thus, it regulates multiple signaling pathways in cell growth, cell polarity and metabolism (Hezel and Bardeesy, 2008;Shackelford and Shaw, 2009;Luo et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Altered LKB1/CREB-regulated transcription co-activator (CRTC) signaling axis promotes esophageal cancer cell migration and invasion

et al. 2011

Oncogene

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LKB1 is a tumor susceptibility gene for the Peutz-Jeghers cancer syndrome and is a target for mutational inactivation in sporadic human malignancies. LKB1 encodes a serine/threonine kinase that has critical roles in cell growth, polarity and metabolism. A novel and important function of LKB1 is its ability to regulate the phosphorylation of CREB-regulated transcription co-activators (CRTCs) whose aberrant activation is linked with oncogenic activities. However, the roles and mechanisms of LKB1 and CRTC in the pathogenesis of esophageal cancer have not been previously investigated. In this study, we observed altered LKB1-CRTC signaling in a subset of human esophageal cancer cell lines and patient samples. LKB1 negatively regulates esophageal cancer cell migration and invasion in vitro. Mechanistically, we determined that CRTC signaling becomes activated because of LKB1 loss, which results in the transcriptional activation of specific downstream targets including LYPD3, a critical mediator for LKB1 loss-of-function. Our data indicate that de-regulated LKB1-CRTC signaling might represent a crucial mechanism for esophageal cancer progression.

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LKB1/KRAS mutant lung cancers constitute a genetic subset of NSCLC with increased sensitivity to MAPK and mTOR signalling inhibition

Cited by 113 publications

References 22 publications

K-ras gene mutation as a predictor of cancer cell responsiveness to metformin

K-ras gene mutation as a predictor of cancer cell responsiveness to metformin

Picking the Point of Inhibition: A Comparative Review of PI3K/AKT/mTOR Pathway Inhibitors

Altered LKB1/CREB-regulated transcription co-activator (CRTC) signaling axis promotes esophageal cancer cell migration and invasion

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