EGF Receptor Signaling Is Essential for K-Ras Oncogene-Driven Pancreatic Ductal Adenocarcinoma

Navas, Carolina; Hernández-Porras, Isabel; Schuhmacher, Alberto J.; Sibilia, Maria; Guerra, Carmen; Barbacid, Mariano

doi:10.1016/j.ccr.2012.08.001

Cited by 347 publications

(384 citation statements)

References 39 publications

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“…10). Although challenging the signalling dogma holding that the GTPase-dependent stimulation of PI3Ka is mostly mediated by direct physical interactions with oncogenic Ras proteins 33 , these results are consistent with previous data indicating that the PI3Ka/Akt axis can be activated in Ras-independent manners in some Ras-transformed cells 16,24,[34][35][36][37] . Interestingly, the influence of R-Ras2 on the PI3K/Akt pathway is highly dependent on the experimental conditions used.…”

Section: R-ras2 Deficient Tumours Develop Compensatory Mechanismssupporting

confidence: 81%

Contribution of the R-Ras2 GTP-binding protein to primary breast tumorigenesis and late-stage metastatic disease

et al. 2014

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R-Ras2 is a transforming GTPase that shares downstream effectors with Ras subfamily proteins. However, little information exists about the function of this protein in tumorigenesis and its signalling overlap with classical Ras GTPases. Here we show, by combining loss-and gain-of-function studies in breast cancer cells, mammary epithelial cells and mouse models, that endogenous R-Ras2 has a role in both primary breast tumorigenesis and the late metastatic steps of cancer cells in the lung parenchyma. R-Ras2 drives tumorigenesis in a phosphatidylinostiol-3 kinase (PI3K)-dependent and signalling autonomous manner. By contrast, its prometastatic role requires other priming oncogenic signals and the engagement of several downstream elements. R-Ras2 function is required even in cancer cells exhibiting constitutive activation of classical Ras proteins, indicating that these GTPases are not functionally redundant. Our results also suggest that application of long-term R-Ras2 therapies will result in the development of compensatory mechanisms in breast tumours.

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Section: R-ras2 Deficient Tumours Develop Compensatory Mechanismssupporting

confidence: 81%

Contribution of the R-Ras2 GTP-binding protein to primary breast tumorigenesis and late-stage metastatic disease

et al. 2014

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“…Along with an ability to overcome inflammation-induced senescence (4), mutants of the RAS gene inevitably up-regulate a plethora of growth factors (e.g., TGF-alpha) and cytokines (e.g., interleukin-8), which likely contribute to disease progression. In line with this possibility, genetically engineered mouse models indicate that development of PDACs driven by KRAS is dependent on EGFR signaling (5). In the same vein, a small-molecule inhibitor of the epidermal growth factor receptor (EGFR) has been approved for the treatment of PDAC (6).…”

mentioning

confidence: 89%

Inhibition of pancreatic carcinoma by homo- and heterocombinations of antibodies against EGF-receptor and its kin HER2/ErbB-2

Maron¹,

Schechter²,

Mancini

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Due to intrinsic aggressiveness and lack of effective therapies, prognosis of pancreatic cancer remains dismal. Because the only molecular targeted drug approved for pancreatic ductal adenocarcinoma is a kinase inhibitor specific to the epidermal growth factor receptor (EGFR), and this receptor collaborates with another kinase, called HER2 (human EGF-receptor 2), we assumed that agents targeting EGFR and/or HER2 would effectively retard pancreatic ductal adenocarcinoma. Accordingly, two immunological strategies were tested in animal models: (i) two antibodies able to engage distinct epitopes of either EGFR or HER2 were separately combined, and (ii) pairs of one antibody to EGFR and another to HER2. Unlike the respective single monoclonal antibodies, which induced weak effects, both types of antibody combinations synergized in animals in terms of tumor inhibition. Immunological cooperation may not depend on receptor density, antigenic sites, or the presence of a mutant RAS protein. Nevertheless, both types of antibody combinations enhanced receptor degradation. Future efforts will examine the feasibility of each strategy and the potential of combining them to achieve sustained tumor inhibition.combination therapy | signal transduction

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“…Firstly, treatment with metformin or silencing Sp transcription factors by RNAi downregulated insulin-like growth factor-1 receptor (IGF-1R), which in turn inhibited activation of mTOR. Secondly, treatment with metformin or silencing Sp transcription factors by RNAi decreased epidermal growth factor receptor (EGFR) expression, resulting in inhibition of Ras activity, which is regulated by EGFR in pancreatic cancer cells (37,38). Thus, we know show for the first time that metformin-dependent inhibition of both mTOR signaling and Ras activity is due to down-regulation of Sp transcription factors in pancreatic cancer.…”

mentioning

confidence: 97%

Mechanism of Metformin-dependent Inhibition of Mammalian Target of Rapamycin (mTOR) and Ras Activity in Pancreatic Cancer

Nair

Sreevalsan

Basha

et al. 2014

Journal of Biological Chemistry

114

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Background: Metformin inhibits pancreatic cancer cell and tumor growth and down-regulated Sp transcription factors. Results: Inhibition of mTOR and Ras signaling by metformin is due to decreased expression of Sp-regulated insulin-like growth factor-1 receptor (IGF-1R) and epidermal growth factor receptor (EGFR), respectively. Conclusion: Metformin-induced down-regulation of Sp proteins affects multiple pro-oncogenic pathways. Significance: These results identify important metformin-induced anticancer activities.

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EGF Receptor Signaling Is Essential for K-Ras Oncogene-Driven Pancreatic Ductal Adenocarcinoma

Cited by 347 publications

References 39 publications

Contribution of the R-Ras2 GTP-binding protein to primary breast tumorigenesis and late-stage metastatic disease

Contribution of the R-Ras2 GTP-binding protein to primary breast tumorigenesis and late-stage metastatic disease

Inhibition of pancreatic carcinoma by homo- and heterocombinations of antibodies against EGF-receptor and its kin HER2/ErbB-2

Mechanism of Metformin-dependent Inhibition of Mammalian Target of Rapamycin (mTOR) and Ras Activity in Pancreatic Cancer

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