Abstract:
:Mutations in PIK3CA, which encodes the p110α subunit of the insulin-activated phosphatidylinositol-3 kinase (PI3K), and loss of function mutations in PTEN, which encodes a phosphatase that degrades the phosphoinositide lipids generated by PI3K, are among the most frequent events in human cancers1,2. However, pharmacological inhibition of PI3K has resulted in variable clinical responses, raising the possibility of an inherent mechanism of resistance to treatment. As p110α mediates virtually all cellular responses to insulin, targeted inhibition of this enzyme disrupts glucose metabolism in multiple tissues. For example, blocking insulin signalling promotes glycogen breakdown in the liver and prevents glucose uptake in the skeletal muscle and adipose tissue, resulting in transient hyperglycaemia within a few hours of PI3K inhibition. The effect is usually transient because compensatory insulin release from the pancreas (insulin feedback) restores normal glucose homeostasis3. However, the hyperglycaemia may be exacerbated or prolonged in patients with any degree of insulin resistance and, in these cases, necessitates discontinuation of therapy3-6. We hypothesized that insulin feedback induced by PI3K inhibitors may reactivate the PI3K-mTOR signalling axis in tumours, thereby compromising treatment effectiveness7,8. Here we show, in several model tumours in mice, that systemic glucose-insulin feedback caused by targeted inhibition of this pathway is sufficient to activate PI3K signalling, even in the presence of PI3K inhibitors. This insulin feedback can be prevented using dietary or pharmaceutical approaches, which greatly enhance the efficacy/toxicity ratios of PI3K inhibitors. These findings have direct clinical implications for the multiple p110α inhibitors that are in clinical trials and provide a way to increase treatment efficacy for patients with many types of tumour.
journal_name
Naturejournal_title
Natureauthors
Hopkins BD,Pauli C,Du X,Wang DG,Li X,Wu D,Amadiume SC,Goncalves MD,Hodakoski C,Lundquist MR,Bareja R,Ma Y,Harris EM,Sboner A,Beltran H,Rubin MA,Mukherjee S,Cantley LCdoi
10.1038/s41586-018-0343-4subject
Has Abstractpub_date
2018-08-01 00:00:00pages
499-503issue
7719eissn
0028-0836issn
1476-4687pii
10.1038/s41586-018-0343-4journal_volume
560pub_type
杂志文章相关文献
NATURE文献大全abstract::Ecological and societal disruptions by modern climate change are critically determined by the time frame over which climates shift beyond historical analogues. Here we present a new index of the year when the projected mean climate of a given location moves to a state continuously outside the bounds of historical vari...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature12540
更新日期:2013-10-10 00:00:00
abstract::The two-dimensional electron system is a powerful laboratory for investigating the physics of interacting particles. Application of a large magnetic field produces massively degenerate quantum levels known as Landau levels; within a Landau level the kinetic energy of the electrons is suppressed, and electron-electron ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature08941
更新日期:2010-03-25 00:00:00
abstract::Increased levels of brain amyloid-beta, a secreted peptide cleavage product of amyloid precursor protein (APP), is believed to be critical in the aetiology of Alzheimer's disease. Increased amyloid-beta can cause synaptic depression, reduce the number of spine protrusions (that is, sites of synaptic contacts) and bloc...
journal_title:Nature
pub_type: 评论,杂志文章
doi:10.1038/nature09217
更新日期:2010-08-12 00:00:00
abstract::Myosin, a major contractile protein, characteristically possesses a long coiled-coil alpha-helical tail and two heads. Each head contains both an actin binding site and an ATPase site and is formed from the NH2-terminal half of one of the two heavy chains (relative molecular mass, Mr, 200,000) and a pair of light chai...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/324078a0
更新日期:1986-11-06 00:00:00
abstract::The nucleotides immediately surrounding intron/exon junctions of genes transcribed by RNA polymerase B can be derived from 'consensus' sequences for donor and acceptor splice sites by only a few base changes. Studies in vivo have underlined the importance of these junction nucleotides for splicing. In higher eukaryote...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/315430a0
更新日期:1985-05-30 00:00:00
abstract::Cells deficient in the Brca1 and Brca2 genes have reduced capacity to repair DNA double-strand breaks by homologous recombination and consequently are hypersensitive to DNA-damaging agents, including cisplatin and poly(ADP-ribose) polymerase (PARP) inhibitors. Here we show that loss of the MLL3/4 complex protein, PTIP...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature18325
更新日期:2016-07-21 00:00:00
abstract::Transmission of obligate bacterial symbionts between generations is vital for the survival of the host. Although the larvae of certain hydrothermal vent tubeworms (Vestimentifera, Siboglinidae) are symbiont-free and possess a transient digestive system, these structures are lost during development, resulting in adult ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature04793
更新日期:2006-05-18 00:00:00
abstract::Large, actively swimming suspension feeders evolved several times in Earth's history, arising independently from groups as diverse as sharks, rays and stem teleost fishes, and in mysticete whales. However, animals occupying this niche have not been identified from the early Palaeozoic era. Anomalocarids, a group of st...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature13010
更新日期:2014-03-27 00:00:00
abstract::The major excitatory amino acids, glutamate (Glu) and aspartate (Asp), are thought to act at three receptor subtypes in the mammalian central nervous system (CNS). These are termed quisqualate (QA), N-methyl-D-aspartate (NMDA) and kainate (KA) receptors according to the specific agonist properties of these compounds r...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/317717a0
更新日期:1985-10-24 00:00:00
abstract::Age-related macular degeneration (AMD), a leading cause of blindness worldwide, is as prevalent as cancer in industrialized nations. Most blindness in AMD results from invasion of the retina by choroidal neovascularisation (CNV). Here we show that the eosinophil/mast cell chemokine receptor CCR3 is specifically expres...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature08151
更新日期:2009-07-09 00:00:00
abstract::Seasonal influenza epidemics are a major public health concern, causing tens of millions of respiratory illnesses and 250,000 to 500,000 deaths worldwide each year. In addition to seasonal influenza, a new strain of influenza virus against which no previous immunity exists and that demonstrates human-to-human transmis...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature07634
更新日期:2009-02-19 00:00:00
abstract::The most unique feature of Earth is the existence of life, and the most extraordinary feature of life is its diversity. Approximately 9 million types of plants, animals, protists and fungi inhabit the Earth. So, too, do 7 billion people. Two decades ago, at the first Earth Summit, the vast majority of the world's nati...
journal_title:Nature
pub_type: 杂志文章,评审
doi:10.1038/nature11148
更新日期:2012-06-06 00:00:00
abstract::The radio sky is relatively unexplored for transient signals, although the potential of radio-transient searches is high. This was demonstrated recently by the discovery of a previously unknown type of source, varying on timescales of minutes to hours. Here we report a search for radio sources that vary on much shorte...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature04440
更新日期:2006-02-16 00:00:00
abstract::Quantum electrodynamics (resulting from the merger of quantum mechanics and relativity theory) has provided a clear understanding of phenomena ranging from particle physics to cosmology and from astrophysics to quantum chemistry. The ideas underlying quantum electrodynamics also influence the theory of condensed matte...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature04233
更新日期:2005-11-10 00:00:00
abstract::Germinal centres are specialized structures wherein B lymphocytes undergo clonal expansion, class switch recombination, antibody gene diversification and affinity maturation. Three to four antigen-specific B cells colonize a follicle to establish a germinal centre and become rapidly dividing germinal-centre centroblas...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature05573
更新日期:2007-03-01 00:00:00
abstract::Although cell adhesion to substrate must ultimately depend on 'sticking' by physical forces at the outer surface, we suggest that control is exercised through the 'grip' of the cytoskeleton. Our experiments indicate that grip can be relaxed by agents which release surface glycoproteins from some form of side-to-side o...
journal_title:Nature
pub_type: 杂志文章,评审
doi:10.1038/267124a0
更新日期:1977-05-12 00:00:00
abstract::The disease non-insulin-dependent (type 2) diabetes mellitus (NIDDM) is characterized by abnormally high blood glucose resulting from a relative deficiency of insulin. It affects about 2% of the world's population and treatment of diabetes and its complications are an increasing health-care burden. Genetic factors are...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/384455a0
更新日期:1996-12-05 00:00:00
abstract::The single endogenous DBA/2J ectropic provirus segregated concordantly with the dilute (d) coat colour mutation on chromosome 9 in 53/53 DBA/2J-derived recombinant inbred mouse strains and all seven inbred and mutant strains tested that carry the d allele. Analysis of DNA from a spontaneous DBA/2J d revertant (d+2J) s...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/293370a0
更新日期:1981-10-01 00:00:00
abstract::The Ran proteins constitute a distinct branch of the superfamily of Ras-related GTP-binding proteins which function as molecular switches cycling between GTP-bound 'on' and GDP-bound 'off' states. Ran is located predominantly in the nucleus of eukaryotic cells and is involved in the nuclear import of proteins as well ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/374378a0
更新日期:1995-03-23 00:00:00
abstract::One goal of regenerative medicine, to use stem cells to replace cells lost by injury or disease, depends on producing an excess of the relevant cell for study or transplantation. To this end, the stepwise differentiation of stem cells into specialized derivatives has been successful for some cell types, but a major pr...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature11463
更新日期:2012-11-29 00:00:00
abstract::Tissue-resident memory T (TRM) cells persist indefinitely in epithelial barrier tissues and protect the host against pathogens. However, the biological pathways that enable the long-term survival of TRM cells are obscure. Here we show that mouse CD8+ TRM cells generated by viral infection of the skin differentially ex...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature21379
更新日期:2017-03-09 00:00:00
abstract::In budding yeast many genes are expressed under cell-cycle control in late G1. These include a large group of DNA synthesis genes, the HO gene involved in mating-type switching, CTS1 (chitinase) and also CLN1 and CLN2 (ref. 4) encoding G1 cyclins. Two factors, encoded by the SWI4 and SWI6 genes, are required for HO (r...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/357505a0
更新日期:1992-06-11 00:00:00
abstract::In addition to coordinating immune and inflammatory responses, NF-kappaB/Rel transcription factors control cell survival. Normally, NF-kappaB dimers are sequestered in the cytoplasm by binding to inhibitory IkappaB proteins, and can be activated rapidly by signals that induce the sequential phosphorylation and proteol...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/35104560
更新日期:2001-11-15 00:00:00
abstract::The Indian Ocean dipole is a prominent mode of coupled ocean-atmosphere variability, affecting the lives of millions of people in Indian Ocean rim countries. In its positive phase, sea surface temperatures are lower than normal off the Sumatra-Java coast, but higher in the western tropical Indian Ocean. During the ext...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature13327
更新日期:2014-06-12 00:00:00
abstract::Spinocerebellar ataxia type 1 (SCA1) is one of several neurodegenerative disorders caused by an expansion of a polyglutamine tract. It is characterized by ataxia, progressive motor deterioration, and loss of cerebellar Purkinje cells. To understand the pathogenesis of SCA1, we examined the subcellular localization of ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/40153
更新日期:1997-10-30 00:00:00
abstract::Protein aggregates are the hallmark of stressed and ageing cells, and characterize several pathophysiological states. Healthy metazoan cells effectively eliminate intracellular protein aggregates, indicating that efficient disaggregation and/or degradation mechanisms exist. However, metazoans lack the key heat-shock p...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature14884
更新日期:2015-08-13 00:00:00
abstract::In the ocean, the chemical forms of nitrogen that are readily available for biological use (known collectively as 'fixed' nitrogen) fuel the global phytoplankton productivity that exports carbon to the deep ocean. Accordingly, variation in the oceanic fixed nitrogen reservoir has been proposed as a cause of glacial-in...
journal_title:Nature
pub_type: 历史文章,杂志文章
doi:10.1038/nature12397
更新日期:2013-09-12 00:00:00
abstract::Much of our knowledge of galaxies comes from analysing the radiation emitted by their stars, which depends on the present number of each type of star in the galaxy. The present number depends on the stellar initial mass function (IMF), which describes the distribution of stellar masses when the population formed, and ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature10972
更新日期:2012-04-25 00:00:00
abstract::The distal lung contains terminal bronchioles and alveoli that facilitate gas exchange. Three-dimensional in vitro human distal lung culture systems would strongly facilitate the investigation of pathologies such as interstitial lung disease, cancer and coronavirus disease 2019 (COVID-19) pneumonia caused by severe ac...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/s41586-020-3014-1
更新日期:2020-12-01 00:00:00
abstract::The evolutionary divergence of a single species into two has never been directly observed in nature, primarily because speciation can take a long time to occur. A ring species, in which a chain of intergrading populations encircles a barrier and the terminal forms coexist without interbreeding, provides a situation in...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/35053059
更新日期:2001-01-18 00:00:00