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1.
Cancer Discov ; 14(8): 1440-1456, 2024 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-38564707

RESUMO

Activating point mutations in the MET tyrosine kinase domain (TKD) are oncogenic in a subset of papillary renal cell carcinomas. Here, using comprehensive genomic profiling among >600,000 patients, we identify activating MET TKD point mutations as putative oncogenic driver across diverse cancers, with a frequency of ∼0.5%. The most common mutations in the MET TKD defined as oncogenic or likely oncogenic according to OncoKB resulted in amino acid substitutions at positions H1094, L1195, F1200, D1228, Y1230, M1250, and others. Preclinical modeling of these alterations confirmed their oncogenic potential and also demonstrated differential patterns of sensitivity to type I and type II MET inhibitors. Two patients with metastatic lung adenocarcinoma harboring MET TKD mutations (H1094Y, F1200I) and no other known oncogenic drivers achieved confirmed partial responses to a type I MET inhibitor. Activating MET TKD mutations occur in multiple malignancies and may confer clinical sensitivity to currently available MET inhibitors. Significance: The identification of targetable genomic subsets of cancer has revolutionized precision oncology and offers patients treatments with more selective and effective agents. Here, we demonstrate that activating, oncogenic MET tyrosine kinase domain mutations are found across a diversity of cancer types and are responsive to MET tyrosine kinase inhibitors.


Assuntos
Neoplasias Pulmonares , Mutação Puntual , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-met , Humanos , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Animais , Camundongos , Linhagem Celular Tumoral
2.
Front Oncol ; 11: 766298, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34900714

RESUMO

Oncoprotein expression is controlled at the level of mRNA translation and is regulated by the eukaryotic translation initiation factor 4F (eIF4F) complex. eIF4A, a component of eIF4F, catalyzes the unwinding of secondary structure in the 5'-untranslated region (5'-UTR) of mRNA to facilitate ribosome scanning and translation initiation. Zotatifin (eFT226) is a selective eIF4A inhibitor that increases the affinity between eIF4A and specific polypurine sequence motifs and has been reported to inhibit translation of driver oncogenes in models of lymphoma. Here we report the identification of zotatifin binding motifs in the 5'-UTRs of HER2 and FGFR1/2 Receptor Tyrosine Kinases (RTKs). Dysregulation of HER2 or FGFR1/2 in human cancers leads to activation of the PI3K/AKT and RAS/ERK signaling pathways, thus enhancing eIF4A activity and promoting the translation of select oncogenes that are required for tumor cell growth and survival. In solid tumor models driven by alterations in HER2 or FGFR1/2, downregulation of oncoprotein expression by zotatifin induces sustained pathway-dependent anti-tumor activity resulting in potent inhibition of cell proliferation, induction of apoptosis, and significant in vivo tumor growth inhibition or regression. Sensitivity of RTK-driven tumor models to zotatifin correlated with high basal levels of mTOR activity and elevated translational capacity highlighting the unique circuitry generated by the RTK-driven signaling pathway. This dependency identifies the potential for rational combination strategies aimed at vertical inhibition of the PI3K/AKT/eIF4F pathway. Combination of zotatifin with PI3K or AKT inhibitors was beneficial across RTK-driven cancer models by blocking RTK-driven resistance mechanisms demonstrating the clinical potential of these combination strategies.

3.
J Med Chem ; 61(8): 3516-3540, 2018 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-29526098

RESUMO

Dysregulated translation of mRNA plays a major role in tumorigenesis. Mitogen-activated protein kinase interacting kinases (MNK)1/2 are key regulators of mRNA translation integrating signals from oncogenic and immune signaling pathways through phosphorylation of eIF4E and other mRNA binding proteins. Modulation of these key effector proteins regulates mRNA, which controls tumor/stromal cell signaling. Compound 23 (eFT508), an exquisitely selective, potent dual MNK1/2 inhibitor, was designed to assess the potential for control of oncogene signaling at the level of mRNA translation. The crystal structure-guided design leverages stereoelectronic interactions unique to MNK culminating in a novel pyridone-aminal structure described for the first time in the kinase literature. Compound 23 has potent in vivo antitumor activity in models of diffuse large cell B-cell lymphoma and solid tumors, suggesting that controlling dysregulated translation has real therapeutic potential. Compound 23 is currently being evaluated in Phase 2 clinical trials in solid tumors and lymphoma. Compound 23 is the first highly selective dual MNK inhibitor targeting dysregulated translation being assessed clinically.


Assuntos
Antineoplásicos/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Piridinas/uso terapêutico , Piridonas/uso terapêutico , Pirimidinas/uso terapêutico , Compostos de Espiro/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Domínio Catalítico , Linhagem Celular Tumoral , Desenho de Fármacos , Fator de Iniciação 4E em Eucariotos/química , Fator de Iniciação 4E em Eucariotos/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Estrutura Molecular , Fosforilação , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Piridinas/síntese química , Piridinas/química , Piridinas/farmacologia , Piridonas/síntese química , Piridonas/química , Piridonas/farmacologia , Pirimidinas/síntese química , Pirimidinas/química , Pirimidinas/farmacologia , Ratos , Serina/química , Transdução de Sinais/efeitos dos fármacos , Compostos de Espiro/síntese química , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
4.
J Invest Dermatol ; 126(1): 154-60, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16417231

RESUMO

Frequent somatic mutation of v-raf murine sarcoma viral oncogene homolog B (BRAF), a downstream effector of the rat sarcoma oncogene (RAS) signaling pathway, is described in melanoma and other tumors. Our analysis of melanoma cell lines suggests that activating mutations in BRAF can occur simultaneously with inactivation of phosphatase and tensin homolog (PTEN), but neuroblastoma RAS (NRAS) mutations are not coincident. We determined the concurrent prevalence of mutations in BRAF and NRAS, and alteration of PTEN expression in 69 primary cutaneous melanomas. BRAF mutations were seen in 57% of cases. NRAS was mutated in 17% of samples, exclusively in exon 2. Two cases showed concurrent BRAF and NRAS mutations. Using immunohistochemistry, PTEN protein expression was lost or greatly reduced in 19% of tumors. Seven tumors with reduced PTEN yielded DNA amenable to sequencing, and three also showed mutation in BRAF but none in NRAS. In all, 11 (85%) of 13 tumors showing reduced PTEN expression were greater than 3.5 mm thick, and the association of increasing Breslow thickness and loss or reduction of PTEN expression was statistically significant (P<0.0001). Mutations in NRAS were not coincident with reduced PTEN expression, and the concurrent mutation of NRAS and BRAF was rare.


Assuntos
Genes ras/genética , Melanoma/genética , PTEN Fosfo-Hidrolase/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Melanoma/química , Melanoma/patologia , Pessoa de Meia-Idade , Mutação , PTEN Fosfo-Hidrolase/análise , Neoplasias Cutâneas/química , Neoplasias Cutâneas/patologia
5.
PLoS One ; 9(5): e96565, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24794217

RESUMO

OBJECTIVE: The immune response to pancreatic ductal adenocarcinoma (PDA) may play a role in defining its uniquely aggressive biology; therefore, we sought to clearly define the adaptive immune infiltrate in PDA. DESIGN: We used immunohistochemistry and flow cytometry to characterize the immune infiltrate in human PDA and compared our findings to the patients' peripheral blood. RESULTS: In contrast to the myeloid cell predominant infiltrate seen in murine models, T cells comprised the majority of the hematopoietic cell component of the tumor stroma in human PDA. Most intratumoral CD8+ T cells exhibited an antigen-experienced effector memory cell phenotype and were capable of producing IFN-γ. CD4+ regulatory T cells (Treg) and IL-17 producing T helper cells were significantly more prevalent in tumor than in blood. Consistent with the association with reduced survival in previous studies, we observed higher frequencies of both myeloid cells and Treg in poorly differentiated tumors. The majority of intratumoral T cells expressed the co-inhibitory receptor programmed death-1 (PD-1), suggesting one potential mechanism through which PDA may evade antitumor immunity. Successful multimodal neoadjuvant therapy altered the immunoregulatory balance and was associated with reduced infiltration of both myeloid cells and Treg. CONCLUSION: Our data show that human PDA contains a complex mixture of inflammatory and regulatory immune cells, and that neoadjuvant therapy attenuates the infiltration of intratumoral cells associated with immunosuppression and worsened survival.


Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/imunologia , Antineoplásicos/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/imunologia , Terapia Neoadjuvante/métodos , Pâncreas/patologia , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Carcinoma Ductal Pancreático/patologia , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Interferon gama/imunologia , Interleucina-17/imunologia , Masculino , Pessoa de Meia-Idade , Pâncreas/efeitos dos fármacos , Pâncreas/imunologia , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Microambiente Tumoral/efeitos dos fármacos
6.
Cancer Cell ; 21(3): 418-29, 2012 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-22439937

RESUMO

Pancreatic ductal adenocarcinomas (PDAs) are characterized by a robust fibroinflammatory response. We show here that this desmoplastic reaction generates inordinately high interstitial fluid pressures (IFPs), exceeding those previously measured or theorized for solid tumors, and induces vascular collapse, while presenting substantial barriers to perfusion, diffusion, and convection of small molecule therapeutics. We identify hyaluronan, or hyaluronic acid (HA), as the primary matrix determinant of these barriers and show that systemic administration of an enzymatic agent can ablate stromal HA from autochthonous murine PDA, normalize IFP, and re-expand the microvasculature. In combination with the standard chemotherapeutic, gemcitabine, the treatment permanently remodels the tumor microenvironment and consistently achieves objective tumor responses, resulting in a near doubling of overall survival.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Desoxicitidina/análogos & derivados , Ácido Hialurônico/fisiologia , Neoplasias Pancreáticas/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Adenocarcinoma/irrigação sanguínea , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Animais , Animais Geneticamente Modificados , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Ductal Pancreático/irrigação sanguínea , Carcinoma Ductal Pancreático/patologia , Moléculas de Adesão Celular/administração & dosagem , Moléculas de Adesão Celular/uso terapêutico , Desoxicitidina/administração & dosagem , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Líquido Extracelular/efeitos dos fármacos , Ácido Hialurônico/metabolismo , Hialuronoglucosaminidase/administração & dosagem , Hialuronoglucosaminidase/farmacologia , Hialuronoglucosaminidase/uso terapêutico , Camundongos , Microvasos/efeitos dos fármacos , Neoplasias Pancreáticas/irrigação sanguínea , Neoplasias Pancreáticas/patologia , Polietilenoglicóis/administração & dosagem , Células Estromais/efeitos dos fármacos , Células Estromais/patologia , Microambiente Tumoral/efeitos dos fármacos , Gencitabina
8.
Proc Natl Acad Sci U S A ; 100(9): 5164-9, 2003 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-12692305

RESUMO

We report the molecular identification of a sialic acid-independent host-parasite interaction in the Plasmodium falciparum malaria parasite invasion of RBCs. Two nonglycosylated exofacial regions of human band 3 in the RBC membrane were identified as a crucial host receptor binding the C-terminal processing products of merozoite surface protein 1 (MSP1). Peptides derived from the receptor region of band 3 inhibited the invasion of RBCs by P. falciparum. A major segment of the band 3 receptor (5ABC) bound to native MSP1(42) and blocked the interaction of native MSP1(42) with intact RBCs in vitro. Recombinant MSP1(19) (the C-terminal domain of MSP1(42)) bound to 5ABC as well as RBCs. The binding of both native MSP1(42) and recombinant MSP1(19) was not affected by the neuraminidase treatment of RBCs, but sensitive to chymotrypsin treatment. In addition, recombinant MSP1(38) showed similar interactions with the band 3 receptor and RBCs, although the interaction was relatively weak. These findings suggest that the chymotrypsin-sensitive MSP1-band 3 interaction plays a role in a sialic acid-independent invasion pathway and reveal the function of MSP1 in the Plasmodium invasion of RBCs.


Assuntos
Proteína 1 de Troca de Ânion do Eritrócito/metabolismo , Eritrócitos/parasitologia , Proteína 1 de Superfície de Merozoito/metabolismo , Plasmodium falciparum/fisiologia , Animais , Eletroforese em Gel de Poliacrilamida , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Dados de Sequência Molecular , Ácido N-Acetilneuramínico/metabolismo , Ligação Proteica , Proteínas Recombinantes/metabolismo
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