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Ref Type | Journal Article | ||||||||||||
PMID | (26483207) | ||||||||||||
Authors | Shen A, Wang L, Huang M, Sun J, Chen Y, Shen YY, Yang X, Wang X, Ding J, Geng M | ||||||||||||
Title | c-Myc alterations confer therapeutic response and acquired resistance to c-Met inhibitors in MET-addicted cancers. | ||||||||||||
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Abstract Text | Use of kinase inhibitors in cancer therapy leads invariably to acquired resistance stemming from kinase reprogramming. To overcome the dynamic nature of kinase adaptation, we asked whether a signal-integrating downstream effector might exist that provides a more applicable therapeutic target. In this study, we reported that the transcriptional factor c-Myc functions as a downstream effector to dictate the therapeutic response to c-Met inhibitors in c-Met-addicted cancer and derived resistance. Dissociation of c-Myc from c-Met control, likely overtaken by a variety of reprogrammed kinases, led to acquisition of drug resistance. Notably, c-Myc blockade by RNA interference or pharmacologic inhibition circumvented the acquired resistance to c-Met inhibition. Combining c-Myc blockade and c-Met inhibition in MET-amplified patient-derived xenograft mouse models heightened therapeutic activity. Our findings offer a preclinical proof of concept for the application of c-Myc-blocking agents as a tactic to thwart resistance to kinase inhibitors. |
Molecular Profile | Treatment Approach |
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Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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