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• W2890450650 endingPage "10063" @default.
• W2890450650 startingPage "10058" @default.
• W2890450650 abstract "Cancer clonal evolution is based on accrual of driving genetic alterations that are expected to cooperate and progressively increase malignancy. Little is known on whether any genetic alteration can hinder the oncogenic function of a coexisting alteration, so that therapeutic targeting of the one can, paradoxically, revive the function of the other. We report the case of a driver oncogene (MET) that is not only bypassed, but also disabled by the mutation of a downstream transducer (BRAF), and reignited by inhibition of the latter. In a metastasis originated from a cancer of unknown primary (CUP), the MET oncogene was amplified eightfold, but unexpectedly, the kinase was dephosphorylated and inactive. As result, specific drugs targeting MET (JNJ-38877605) failed to inhibit growth of xenografts derived from the patient. In addition to MET amplification, the patient harbored, as sole proliferative driver, a mutation hyperactivating BRAF (G469A). Surprisingly, specific blockade of the BRAF pathway was equally ineffective, and it was accompanied by rephosphorylation of the amplified MET oncoprotein and by revived addiction to MET. Mechanistically, MET inactivation in the context of the BRAF-activating mutation is driven through a negative feedback loop involving inactivation of PP2A phosphatase, which in turn leads to phosphorylation on MET inhibitory Ser985. Disruption of this feedback loop allows PP2A reactivation, removing the inhibitory phosphorylation from Ser985 and thereby unleashing MET kinase activity. Evidence is provided for a mechanism of therapeutic resistance to single-oncoprotein targeting, based on reactivation of a genetic alteration functionally dormant in targeted cancer cells." @default.
• W2890450650 created "2018-09-27" @default.
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• W2890450650 creator A5057214666 @default.
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• W2890450650 creator A5074714791 @default.
• W2890450650 date "2018-09-17" @default.
• W2890450650 modified "2023-10-03" @default.
• W2890450650 title "Reviving oncogenic addiction to MET bypassed by BRAF (G469A) mutation" @default.
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• W2890450650 doi "https://doi.org/10.1073/pnas.1721147115" @default.
• W2890450650 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6176587" @default.
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• W2890450650 hasPublicationYear "2018" @default.
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