Cotargeting MNK and MEK kinases induces the regression of NF1-mutant cancers

Lock, Rebecca; Ingraham, Rachel; Maertens, Ophélia; Miller, Abigail; Weledji, Nelly; Legius, Eric; Konicek, Bruce M.; Graff, Jeremy R.; Cichowski, Karen

doi:10.1172/jci85183

Cited by 37 publications

(44 citation statements)

References 27 publications

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“…Our study, and the work of others (38,39,48,49), strongly support the preclinical development of MNK1/2 inhibitors for the treatment of patients with melanoma, and potentially other malignancies harboring KIT aberrations.…”

Section: Discussionsupporting

confidence: 73%

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MNK1/2 inhibition limits oncogenicity and metastasis of KIT-mutant melanoma

Yao

Guo

Yang

et al. 2017

Journal of Clinical Investigation

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Section: Discussionsupporting

confidence: 73%

“…The data described herein add melanoma to the growing list of malignancies with aberrant MNK1/2 activity (37)(38)(39)(40). This work has led to several insights into the biology of melanomas wherein KIT is mutated.…”

Section: Discussionmentioning

confidence: 80%

MNK1/2 inhibition limits oncogenicity and metastasis of KIT-mutant melanoma

Yao

Guo

Yang

et al. 2017

Journal of Clinical Investigation

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“…Sapanisertib was used because mTOR kinase inhibitors more effectively inhibit 4E-BP1 phosphorylation in these cells in vitro as compared to rapamycin (19), similar to observations in other cell lines (21,22), and because the 4E-BP/eIF4E pathway has been shown to be particularly important for MPNSTs (23). As previously reported, sapanisertib slowed the proliferation of MPNSTs, but cells did not die (23); however when combined, sapanisertib and vorinostat potently killed MPNSTs (Fig. 1B).…”

Section: Resultsmentioning

confidence: 99%

“…Unless otherwise indicated, drug concentrations were as follows: vorinostat (2μM), romidepsin (1nM), panobinostat (20nM), sapanisertib (200nM for all cell lines except 90-8TLs, where sapanisertib was used at 100nM), auranofin (750nM), buthionine sulfoximine (200 μM). The concentration of sapanisertib (200nM) was chosen based on previously published studies (23,56,57). 100nM was used in 90-8TLs for historical reasons but 200nM produces the same results.…”

Section: Methodsmentioning

confidence: 99%

mTOR and HDAC Inhibitors Converge on the TXNIP/Thioredoxin Pathway to Cause Catastrophic Oxidative Stress and Regression of RAS-Driven Tumors

et al. 2017

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While agents that inhibit specific oncogenic kinases have been successful in a subset of cancers, there are currently few treatment options for malignancies that lack a targetable oncogenic driver. Nevertheless, during tumor evolution cancers engage a variety of protective pathways, which may provide alternative actionable dependencies. Here we identify a promising combination therapy that kills NF1-mutant tumors by triggering catastrophic oxidative stress. Specifically, we show that mTOR and HDAC inhibitors kill aggressive nervous system malignancies and shrink tumors in vivo by converging on the TXNIP/thioredoxin anti-oxidant pathway, through cooperative effects on chromatin and transcription. Accordingly, TXNIP triggers cell death by inhibiting thioredoxin and activating Apoptosis Signal-regulating Kinase 1 (ASK1). Moreover, this drug combination also kills NF1-mutant and KRAS-mutant non-small cell lung cancers. Together these studies identify a promising therapeutic combination for several currently untreatable malignancies, and reveal a protective nodal point of convergence between these important epigenetic and oncogenic enzymes.

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“…Additional trials are ongoing in this population with imatinib (NCT01140360, NCT02177825 and NCT01673009), and a broader trial is evaluating the effects of cabozantinib (Exelixis). Interestingly, while cabozantinib inhibits c-KIT, it also inhibits additional kinases, including MNK, a newly identified in MPNSTs that, when suppressed, synergizes with MEK inhibitors (26). Finally, macrophages are also important for the maintenance of plexiform neurofibromas (27).…”

Section: Successful Target Identification and Translationmentioning

confidence: 99%

A Collaborative Model for Accelerating the Discovery and Translation of Cancer Therapies

et al. 2017

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Preclinical studies using genetically engineered mouse models (GEMMs) have the potential to expedite the development of effective new therapies; however, they are not routinely integrated into drug development pipelines. GEMMs may be particularly valuable for investigating treatments for less common cancers, which frequently lack alternative faithful models. Here we describe a multi-center cooperative group that has successfully leveraged the expertise and resources from philanthropic foundations, academia, and industry to advance therapeutic discovery and translation using GEMMs as a preclinical platform. This effort, known as the Neurofibromatosis Preclinical Consortium (NFPC), was established to accelerate new treatments for tumors associated with neurofibromatosis type 1 (NF1). At its inception, there were no effective treatments for NF1 and few promising approaches on the horizon. Since 2008 participating labs have conducted 95 preclinical trials of 38 drugs or combinations through collaborations with 18 pharmaceutical companies. Importantly, these studies have identified 13 therapeutic targets, which have inspired 16 clinical trials. This review outlines the opportunities and challenges of building this type of consortium and highlights how it can accelerate clinical translation. We believe that this strategy of foundation-academic-industry partnering is generally applicable to many diseases and has the potential to markedly improve the success of therapeutic development.

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Cotargeting MNK and MEK kinases induces the regression of NF1-mutant cancers

Cited by 37 publications

References 27 publications

MNK1/2 inhibition limits oncogenicity and metastasis of KIT-mutant melanoma

MNK1/2 inhibition limits oncogenicity and metastasis of KIT-mutant melanoma

mTOR and HDAC Inhibitors Converge on the TXNIP/Thioredoxin Pathway to Cause Catastrophic Oxidative Stress and Regression of RAS-Driven Tumors

A Collaborative Model for Accelerating the Discovery and Translation of Cancer Therapies

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