Reviving oncogenic addiction to MET bypassed by BRAF (G469A) mutation

Proceedings of the National Academy of Sciences of the United States of America
Anna Rita VirzìPaolo Maria Comoglio

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 ne...Continue Reading

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Citations

Jun 12, 2020·Nature Communications·Ravi S NarayanBart A Westerman
Aug 9, 2020·Signal Transduction and Targeted Therapy·Xing HuangTingbo Liang
Apr 23, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Natalia Magdalena ChrzanowskaMarzena Anna Lewandowska
May 26, 2021·Oncogene·Marie FernandesDavid Tulasne
Jul 14, 2021·Molecular Cancer Therapeutics·Tamara MirzapoiazovaRavi Salgia

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Methods Mentioned

BETA
xenografts
Assay
transfection
PCR
Profiler

Clinical Trials Mentioned

NCT03347318

Software Mentioned

Summit
GraphPad Prism
OncoCarta
ImageJ

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