Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor

Rodrik-Outmezguine, Vanessa; Okaniwa, Masanori; Yao, Zhan; Novotny, Chris J.; McWhirter, Claire; Banaji, Arpitha; Won, Helen; Wong, Wai Lin; Berger, Mike; Stanchina, Elisa de; Barratt, Derek; Cosulich, Sabina C.; Klinowska, Teresa; Rosen, Neal; Shokat, Kevan M.

doi:10.1038/nature17963

Cited by 380 publications

(415 citation statements)

References 28 publications

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“…may be with the recently described "third-generation" mTOR inhibitor called "RapaLink," in which the ATP-competitive mTOR inhibitor is chemically linked to rapamycin, enabling inhibition of mTOR mutants that are resistant to either MLN0128 or rapamycin alone (Rodrik-Outmezguine et al, 2016).…”

Section: Mtor In Cancermentioning

confidence: 99%

mTOR Signaling in Growth, Metabolism, and Disease

Saxton

Sabatini

2017

Cell

2,272

2,558

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The mechanistic Target of Rapamycin (mTOR) coordinates eukaryotic cell growth and metabolism with environmental inputs including nutrients and growth factors. Extensive research over the past two decades has established a central role for mTOR in regulating many fundamental cell processes, from protein synthesis to autophagy, and deregulated mTOR signaling is implicated in the progression of cancer and diabetes, as well as the aging process. Here, we review recent advances in our understanding of mTOR function, regulation, and importance in mammalian physiology. We also highlight how the mTOR-signaling network contributes to human disease, and discuss the current and future prospects for therapeutically targeting mTOR in the clinic.

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Section: Mtor In Cancermentioning

confidence: 99%

mTOR Signaling in Growth, Metabolism, and Disease

Saxton

Sabatini

2017

Cell

2,272

2,558

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“…Type II inhibitors introduce additional specificity by binding not only the ATP pocket but also an adjacent allosteric pocket [106,107]. The recently solved crystal structure of the mTOR kinase domain in complex with ATP-competitive inhibitor, PP242, will no doubt facilitate the design and synthesis of further catalytic mTOR inhibitors [108,109]. It is important to note that at this time there are no FDA approved drugs which specifically act on MNK kinases, and little progress has been made since the discovery of CGP57380, which exhibits low micromolar MNK inhibition [110].…”

Section: Therapeutic Targeting and The Concept Of Hybrid Inhibitorsmentioning

confidence: 99%

Dual Abrogation of Mnk and Mtor: A Novel Therapeutic Approach for the Treatment of Aggressive Cancers

2017

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Targeting the translational machinery has emerged as a promising therapeutic option for cancer treatment. Cancer cells require elevated protein synthesis and exhibit augmented activity to meet the increased metabolic demand. Eukaryotic translation initiation factor 4E is necessary for mRNA translation, its availability and phosphorylation are regulated by the PI3K/AKT/mTOR and MNK1/2 pathways. The phosphorylated form of eIF4E drives the expression of oncogenic proteins including those involved in metastasis. In this article, we will review the role of eIF4E in cancer, its regulation and discuss the benefit of dual inhibition of upstream pathways. The discernible interplay between the MNK and mTOR signaling pathways provides a novel therapeutic opportunity to target aggressive migratory cancers through the development of hybrid molecules.

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“…One drug, a third-generation mTOR complex 1 (mTORC1) is a selective inhibitor that provides dual-site inhibition of mTORC1 (protein-protein binding of rapamycin combined with an ATP site inhibitor) [18]. The inhibitor crossed the BBB and achieved tumor growth inhibition in a genetically engineered mouse model (GEMM) with an intact BBB.…”

Section: Drug Targets and Brain Penetrant Drugsmentioning

confidence: 99%

CNS Anticancer Drug Discovery and Development: 2016 conference insights

Levin

Abrey

Heffron³

et al. 2017

CNS Oncol.

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The 2016 second CNS Anticancer Drug Discovery and Development Conference addressed diverse viewpoints about why new drug discovery/development focused on CNS cancers has been sorely lacking. Despite more than 70,000 individuals in the USA being diagnosed with a primary brain malignancy and 151,669-286,486 suffering from metastatic CNS cancer, in 1999, temozolomide was the last drug approved by the US FDA as an anticancer agent for high-grade gliomas. Among the topics discussed were economic factors and pharmaceutical risk assessments, regulatory constraints and perceptions and the need for improved imaging surrogates of drug activity. Included were modeling tumor growth and drug effects in a medical environment in which direct tumor sampling for biological effects can be problematic, potential new drugs under investigation and targets for drug discovery and development. The long trajectory and diverse impediments to novel drug discovery, and expectation that more than one drug will be needed to adequately inhibit critical intracellular tumor pathways were viewed as major disincentives for most pharmaceutical/ biotechnology companies. While there were a few unanimities, one consensus is the need for continued and focused discussion among academic and industry scientists and clinicians to address tumor targets, new drug chemistry, and more time-and cost-efficient clinical trials based on surrogate end points.

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Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor

Cited by 380 publications

References 28 publications

mTOR Signaling in Growth, Metabolism, and Disease

mTOR Signaling in Growth, Metabolism, and Disease

Dual Abrogation of Mnk and Mtor: A Novel Therapeutic Approach for the Treatment of Aggressive Cancers

CNS Anticancer Drug Discovery and Development: 2016 conference insights

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