Expression of pEGFR and pAKT as response-predictive biomarkers for RAS wild-type patients to anti-EGFR monoclonal antibodies in metastatic colorectal cancers

Harlé, Alexandre; Salleron, Julia; Perkins, Géraldine; Pilati, Camilla; Laurent‐Puig, Pierre; Merlin, Jean‐Louis

doi:10.1038/bjc.2015.250

Cited by 11 publications

(6 citation statements)

References 26 publications

(34 reference statements)

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“…Thus, patients with activated cell surface receptors (notably EGFR) and PI3K pathway are more likely to respond to anti-EGFR therapy. Our data confirm and extent previously reported observations on the predictive value of phospho-EGFR and phospho-Akt ( Van Schaeybroeck et al , 2005 ; Harle et al , 2015 ).…”

Section: Discussionsupporting

confidence: 93%

Protein biomarkers predictive for response to anti-EGFR treatment in RAS wild-type metastatic colorectal carcinoma

et al. 2017

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Background:Metastatic colorectal cancer (mCRC) patients with mutant KRAS or NRAS are ineligible for anti-epidermal growth factor receptor (anti-EGFR) therapy, as RAS mutations activate downstream pathways independently of EGFR and induce primary resistance. However, even among RAS wild-type (WT) patients, only a fraction responds to anti-EGFR therapy, suggesting that other mechanisms of resistance exist. We hypothesise that different (epi)genetic alterations can lead to primary anti-EGFR resistance and that the crucial end point is the activation of protein signalling pathways.Methods:We analysed the expression and activation of proteins involved in cell signalling, using reverse phase protein arrays, on a multicentre French cohort of RAS WT mCRC treated with anti-EGFR treatment.Results:We identify activated EGFR and HER3 as protein biomarkers predictive for better overall survival. Active EGFR signalling and downstream PI3K, but not MAPK, pathway activation are associated with response to anti-EGFR treatment. Left-sided mCRC displays active ErbB2/3 and Wnt pathways and a better response to anti-EGFR therapy compared to right-sided mCRC.Conclusions:We identify active EGFR and PI3K signalling as a key factor for response to anti-EGFR treatment in mCRC and highlight the importance of developing these biomarkers in clinical practice for the selection of RAS WT mCRC patients that would benefit from anti-EGFR treatment.

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Section: Discussionsupporting

confidence: 93%

Protein biomarkers predictive for response to anti-EGFR treatment in RAS wild-type metastatic colorectal carcinoma

et al. 2017

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“…However, in one of our previous studies, we presented in vitro data suggesting that a high level of activated EGFR is associated with a good response to cetuximab . Furthermore, several other studies have suggested that cells are sensitive to EGFR inhibition only if they are dependent on EGFR for Akt activation, cell survival, and growth . However, in this study, we could not find any correlation between EGFR and Akt activation or between Akt activation and cetuximab sensitivity.…”

Section: Discussioncontrasting

confidence: 85%

Cetuximab sensitivity of head and neck squamous cell carcinoma xenografts is associated with treatment‐induced reduction in EGFR, pEGFR, and pSrc

Jedliński¹,

Garvin

Johansson

et al. 2017

J Oral Pathology Medicine

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“…Recently, several investigators argued the possibility of personalized therapy by evaluating the specific signalling activation state of tyrosine kinases in different types of malignancies, including lung carcinoma [ 40 ], colorectal carcinoma [ 41 ] and ovarian carcinoma [ 42 ]. Most recently, we have reported that c-MET phosphorylation in clinical samples is a potential biomarker predicting response to a selective c-MET inhibitor for SS patients [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

Therapeutic potential of TAS-115 via c-MET and PDGFRα signal inhibition for synovial sarcoma

et al. 2017

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BackgroundThe prognosis of synovial sarcoma (SS), an aggressive soft tissue sarcoma, remains poor. We previously reported that c-MET or platelet-derived growth factor receptor α (PDGFRα) signalling pathway is related to SS progression based upon the findings of phospho-receptor tyrosine kinase (RTK) arrays. TAS-115 is a novel c-MET/ vascular endothelial growth factor receptor-targeting tyrosine kinase inhibitor that has been shown to inhibit multiple RTKs. Here we aimed to investigate the therapeutic potential of TAS-115 against SS.MethodsWe first evaluated which signalling pathway was relevant to the viability of three human SS cell lines: Yamato-SS, SYO-1 and HS-SY-II. Next, we assessed the anticancer activity and mechanism of action of TAS-115 in these SS cell lines. Finally, we compared the ability of TAS-115 to inhibit c-MET and PDGFRα phosphorylation with that of pazopanib.ResultsWe classified the SS cell lines as c-MET-dependent or PDGFRα-dependent based upon the differences in the signalling pathway relevant for growth and/or survival. We also found that c-MET and PDGFRα were the primary activators of both phosphatidylinositol 3-kinase/AKT and mitogen-activated protein kinase pathways in c-MET-dependent and PDGFRα-dependent SS cells, respectively. TAS-115 treatment blocked the phosphorylation of PDGFRα as well as that of c-MET and their downstream effectors, leading to marked growth inhibition in both types of SS cell lines in in vitro and in vivo studies. Furthermore, PDGFRα phosphorylation, on at least four representative autophosphorylation sites, was impeded by TAS-115 equivalently to pazopanib.ConclusionsThese experimental results have demonstrated the significance of c-MET and PDGFRα signalling for growth and/or survival of SS tumours. TAS-115 monotherapy may benefit SS patients whose tumours are dependent upon either c-MET or PDGFRα signalling by functioning as a multiple tyrosine kinase inhibitor to suppress c-MET as well as PDGFRα pathways.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3324-3) contains supplementary material, which is available to authorized users.

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Expression of pEGFR and pAKT as response-predictive biomarkers for RAS wild-type patients to anti-EGFR monoclonal antibodies in metastatic colorectal cancers

Cited by 11 publications

References 26 publications

Protein biomarkers predictive for response to anti-EGFR treatment in RAS wild-type metastatic colorectal carcinoma

Protein biomarkers predictive for response to anti-EGFR treatment in RAS wild-type metastatic colorectal carcinoma

Cetuximab sensitivity of head and neck squamous cell carcinoma xenografts is associated with treatment‐induced reduction in EGFR, pEGFR, and pSrc

Therapeutic potential of TAS-115 via c-MET and PDGFRα signal inhibition for synovial sarcoma

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