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1.
Cell Chem Biol ; 30(10): 1211-1222.e5, 2023 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-37827156

RESUMO

The small-molecule drug ralimetinib was developed as an inhibitor of the p38α mitogen-activated protein kinase, and it has advanced to phase 2 clinical trials in oncology. Here, we demonstrate that ralimetinib resembles EGFR-targeting drugs in pharmacogenomic profiling experiments and that ralimetinib inhibits EGFR kinase activity in vitro and in cellulo. While ralimetinib sensitivity is unaffected by deletion of the genes encoding p38α and p38ß, its effects are blocked by expression of the EGFR-T790M gatekeeper mutation. Finally, we solved the cocrystal structure of ralimetinib bound to EGFR, providing further evidence that this drug functions as an ATP-competitive EGFR inhibitor. We conclude that, though ralimetinib is >30-fold less potent against EGFR compared to p38α, its ability to inhibit EGFR drives its primary anticancer effects. Our results call into question the value of p38α as an anticancer target, and we describe a multi-modal approach that can be used to uncover a drug's mechanism-of-action.


Assuntos
Neoplasias Pulmonares , Proteína Quinase 14 Ativada por Mitógeno , Humanos , Receptores ErbB , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Mutação , Proteína Quinase 14 Ativada por Mitógeno/genética , Proteína Quinase 14 Ativada por Mitógeno/metabolismo
2.
Cancer Discov ; 13(5): 1250-1273, 2023 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-37067901

RESUMO

Cancer-relevant mutations in the oligomerization domain (OD) of the p53 tumor suppressor protein, unlike those in the DNA binding domain, have not been well elucidated. Here, we characterized the germline OD mutant p53(A347D), which occurs in cancer-prone Li-Fraumeni syndrome (LFS) patients. Unlike wild-type p53, mutant p53(A347D) cannot form tetramers and exists as a hyperstable dimeric protein. Further, p53(A347D) cannot bind or transactivate the majority of canonical p53 target genes. Isogenic cell lines harboring either p53(A347D) or no p53 yield comparable tumorigenic properties, yet p53(A347D) displays remarkable neomorphic activities. Cells bearing p53(A347D) possess a distinct transcriptional profile and undergo metabolic reprogramming. Further, p53(A347D) induces striking mitochondrial network aberration and associates with mitochondria to drive apoptotic cell death upon topoisomerase II inhibition in the absence of transcription. Thus, dimer-forming p53 demonstrates both loss-of-function (LOF) and gain-of-function (GOF) properties compared with the wild-type form of the protein. SIGNIFICANCE: A mutant p53 (A347D), which can only form dimers, is associated with increased cancer susceptibility in LFS individuals. We found that this mutant wields a double-edged sword, driving tumorigenesis through LOF while gaining enhanced apoptogenic activity as a new GOF, thereby yielding a potential vulnerability to select therapeutic approaches. See related commentary by Stieg et al., p. 1046. See related article by Gencel-Augusto et al., p. 1230. This article is highlighted in the In This Issue feature, p. 1027.


Assuntos
Síndrome de Li-Fraumeni , Humanos , Síndrome de Li-Fraumeni/genética , Síndrome de Li-Fraumeni/metabolismo , Síndrome de Li-Fraumeni/patologia , Ativação Transcricional , Proteína Supressora de Tumor p53/metabolismo , Apoptose/genética , Mitocôndrias/metabolismo
3.
New Dir Stud Leadersh ; 2019(162): 91-109, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31066501

RESUMO

This chapter describes a model for elevating students as colleagues driven by student leadership development. Treating students as colleagues allows organizations to transcend traditional employment roles, and to develop leadership identity while preparing students for leadership as professionals.


Assuntos
Emprego , Liderança , Competência Profissional , Estudantes , Universidades , Adulto , Humanos , Adulto Jovem
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