RAS interaction with PI3K p110α is required for tumor-induced angiogenesis

Murillo, Miguel; Zelenay, Santiago; Nye, Emma; Castellano, Esther; Lassailly, François; Stamp, Gordon; Downward, Julian

doi:10.1172/jci74134

Cited by 70 publications

(75 citation statements)

References 54 publications

(52 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These results are also in agreement with Hoeflich and colleagues (55) and Iadevaia and colleagues (56) who predicted synergistic cell killing of basal-like (triple-negative) breast carcinoma following dual blockade of MAPK and PI3K. Likewise, Engelman and colleagues (33) demonstrated that combined pathway signaling is required for Ras-dependent tumor initiation, whereas Downward and colleagues found that dual pathway activation is required for Ras-dependent tumor maintenance (42) and angiogenesis (43). Interestingly, LbL nanoparticle encapsulation further improved synergistic cell killing in MDA-MB-231 cells by 2.6-fold, consistent with simultaneous blockade of pErk1/2 and pAkt staining as measured by immunofluorescence cytometry (Fig.…”

Section: Resultssupporting

confidence: 87%

See 1 more Smart Citation

Tumor-Targeted Synergistic Blockade of MAPK and PI3K from a Layer-by-Layer Nanoparticle

Dreaden

Kong

Morton

et al. 2015

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose Cross-talk and feedback between the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR cell signaling pathways is critical for tumor initiation, maintenance, and adaptive resistance to targeted therapy in a variety of solid tumors. Combined blockade of these pathways—horizontal blockade—is a promising therapeutic strategy; however, compounded dose-limiting toxicity of free small molecule inhibitor combinations is a significant barrier to its clinical application. Experimental Design AZD6244 (selumetinib), an allosteric inhibitor of Mek1/2, and PX-866, a covalent inhibitor of PI3K, were co-encapsulated in a tumor-targeting nanoscale drug formulation—layer-by-layer (LbL) nanoparticles. Structure, size, and surface charge of the nanoscale formulations were characterized, in addition to in vitro cell entry, synergistic cell killing, and combined signal blockade. In vivo tumor targeting and therapy was investigated in breast tumor xenograft-bearing NCR nude mice by live animal fluorescence/bioluminescence imaging, Western blotting, serum cytokine analysis, and immunohistochemistry. Results Combined MAPK and PI3K axis blockade from the nanoscale formulations (160 ± 20 nm, −40 ± 1 mV) was synergistically toxic toward triple-negative breast (MDA-MB-231) and RAS-mutant lung tumor cells (KP7B) in vitro, effects that were further enhanced upon encapsulation. In vivo, systemically administered LbL nanoparticles preferentially targeted subcutaneous MDA-MB-231 tumor xenografts, simultaneously blocked tumor-specific phosphorylation of the terminal kinases Erk and Akt, and elicited significant disease stabilization in the absence of dose-limiting hepatotoxic effects observed from the free drug combination. Mice receiving untargeted, but dual drug-loaded nanoparticles exhibited progressive disease. Conclusions Tumor-targeting nanoscale drug formulations could provide a more safe and effective means to synergistically block MAPK and PI3K in the clinic.

show abstract

Section: Resultssupporting

confidence: 87%

“…Conversely, augmented PI3K signaling has been shown to contribute to resistance toward EGFR (39), BRAF (40), and MEK (41) inhibitors. PI3K signaling is also known to predicate maintenance of RAS-dependent lung tumors (33, 42), and cross-talk between these 2 pathways is known to be required for RAS-dependent angiogenesis (43). …”

Section: Introductionmentioning

confidence: 99%

Tumor-Targeted Synergistic Blockade of MAPK and PI3K from a Layer-by-Layer Nanoparticle

Dreaden

Kong

Morton

et al. 2015

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…However, mammalian RAS proteins have other important effectors, of which PI 3-kinase (PI3K) is the best validated. For example, Catellano et al (2013) and Gupta et al (2007) generated mice expressing a mutant form of PI3Kα that fails to bind RAS: most of these mice did not survive to adulthood and those that did had defective lymphatic systems and were defective in angiogenesis and in macrophage function (Murillo et al, 2014). This interaction is, therefore, essential, albeit in specific tissue types.…”

Section: Ras Effectorsmentioning

confidence: 99%

RAS Proteins and Their Regulators in Human Disease

Simanshu

Nissley

McCormick

2017

Cell

1,311

1,298

View full text Add to dashboard Cite

RAS proteins are binary switches, cycling between ON and OFF states during signal transduction. These switches are normally tightly controlled, but in RAS-related diseases, such as cancer, RASopathies, and many psychiatric disorders, mutations in the RAS genes or their regulators render RAS proteins persistently active. The structural basis of the switch and many of the pathways that RAS controls are well known, but the precise mechanisms by which RAS proteins function are less clear. All RAS biology occurs in membranes: a precise understanding of RAS’ interaction with membranes is essential to understand RAS action and to intervene in RAS-driven diseases.

show abstract

“…This type of vascular aberration upon PI3K inhibition differs from vascular endothelial growth factor-centred antiangiogenesis therapies, which mainly lead to vascular pruning. Murillo et al demonstrated that functional interaction between Kras and p110a in host tissue is essential for efficient establishment and growth of metastatic tumours (Murillo et al, 2014). Inhibition of this interaction prevented efficient angiogenesis through the regulation of VEGF-A and FGF-2 production.…”

Section: Pi3k/akt Signalling and Pancreatic Cancer Microenvironmentmentioning

confidence: 99%

“…This modification upon PI3K signalling inactivation in the tumour-surrounding cells contributes to form a less tumourpermissive environment (Murillo et al, 2014). The PI3K p110g expressed in immune cells is required for tumour inflammation, growth and metastasis.…”

Section: Pi3k/akt Signalling and Pancreatic Cancer Microenvironmentmentioning

confidence: 99%

Implication of PI3K/Akt pathway in pancreatic cancer: When PI3K isoforms matter?

Baer

Cintas

Therville

et al. 2015

Advances in Biological Regulation

View full text Add to dashboard Cite

RAS interaction with PI3K p110α is required for tumor-induced angiogenesis

Cited by 70 publications

References 54 publications

Tumor-Targeted Synergistic Blockade of MAPK and PI3K from a Layer-by-Layer Nanoparticle

Tumor-Targeted Synergistic Blockade of MAPK and PI3K from a Layer-by-Layer Nanoparticle

RAS Proteins and Their Regulators in Human Disease

Implication of PI3K/Akt pathway in pancreatic cancer: When PI3K isoforms matter?

Contact Info

Product

Resources

About