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1.
Ther Adv Med Oncol ; 11: 1758835919833867, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31205497

RESUMO

Drug-drug interactions are of significant concern in clinical practice in oncology, particularly in patients receiving Cyclin-dependent kinase (CDK) 4/6 inhibitors, which are typically exposed to long-term regimens. This article presents the highlights from the 'First Workshop on Pharmacology and Management of CDK4/6 Inhibitors: Consensus about Concomitant Medications'. The article is structured into two modules. The educational module includes background information regarding drug metabolism, corrected QT (QTc) interval abnormalities, management of psychotropic drugs and a comprehensive review of selected adverse effects of palbociclib and ribociclib. The collaborative module presents the conclusions of the five working groups, each of which comprised five experts from different fields. From these conclusions positive lists of drugs for treating common comorbid conditions that can be safely administered concomitantly with palbociclib and/or ribociclib were developed.

2.
Clin Cancer Res ; 21(3): 569-76, 2015 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-25467182

RESUMO

PURPOSE: Expression of p95HER2 has been associated with resistance to trastuzumab-based therapy in patients with metastatic breast cancer. Conversely, high levels of HER2 have been linked with increased clinical benefit from anti-HER2 therapy. In this work, we aimed to investigate whether the levels of p95HER2 and HER2 can predict response to anti-HER2 therapy in patients with breast cancer. EXPERIMENTAL DESIGN: We measured p95HER2 and HER2 by VeraTag and HERmark, respectively, in primary tumors of patients enrolled in the neoadjuvant phase III study NeoALTTO and correlated these variables with pathologic complete response (pCR) and progression-free survival (PFS) following lapatinib (L), trastuzumab (T), or the combination of both agents (L+T). RESULTS: A positive correlation between p95HER2 and HER2 levels was found in the 274 cases (60%) in which quantification of both markers was possible. High levels of these markers were predictive for pCR, especially in the hormone receptor (HR)-positive subset of patients. High HER2 expression was associated with increased pCR rate upon L+T irrespective of the HR status. To examine whether the levels of either p95HER2 or HER2 could predict for PFS in patients treated with lapatinib, trastuzumab or L+T, we fit to the PFS data in Cox models containing log2(p95HER2) or log2(HER2). Both variables correlated with longer PFS. CONCLUSIONS: Increasing HER2 protein expression correlated with increased benefit of adding lapatinib to trastuzumab. HER2 expression is a stronger predictor of pCR and PFS than p95HER2 for response to lapatinib, trastuzumab and, more significantly, L+T.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Receptor ErbB-2/metabolismo , Anticorpos Monoclonais Humanizados/administração & dosagem , Biópsia , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Feminino , Expressão Gênica , Humanos , Lapatinib , Terapia Neoadjuvante , Quinazolinas/administração & dosagem , Receptor ErbB-2/genética , Trastuzumab , Resultado do Tratamento
3.
Cancer Discov ; 3(11): 1238-44, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23950206

RESUMO

UNLABELLED: Genomic characterization of recurrent breast and lung tumors developed over the course of 10 years in a 29-year-old patient with a germline TP53 mutation (Li-Fraumeni Syndrome) identified oncogenic alterations in the HER2 and EGFR genes across all tumors, including HER2 amplifications, an EGFR-exon 20 insertion, and the first-in-humans HER2V659E mutation showing a phenotypic convergent evolution toward HER2 and EGFR alterations. Following the identification of HER2-activating events in the most recent lung carcinoma and in circulating tumor cells, we treated the reminiscent metastatic lesions with a lapatinib-based therapy. A symptomatic and radiologic clinical response was achieved. HER2V659E sensitivity to lapatinib was confirmed in the laboratory. SIGNIFICANCE: The precise knowledge of the genomic alterations present in tumors is critical to selecting the optimal treatment for each patient. Here, we report the molecular characterization and clinical response to a lapatinib-based therapy for the tumors of a Li-Fraumeni patient showing prevalence of HER2 and EGFR genomic alterations.


Assuntos
Síndrome de Li-Fraumeni/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Receptor ErbB-2/genética , Adulto , Exoma , Feminino , Humanos , Lapatinib , Síndrome de Li-Fraumeni/genética , Síndrome de Li-Fraumeni/metabolismo , Síndrome de Li-Fraumeni/patologia , Mutação , Metástase Neoplásica , Receptor ErbB-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas
4.
J Clin Invest ; 123(6): 2551-63, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23635776

RESUMO

The PI3K signaling pathway regulates diverse cellular processes, including proliferation, survival, and metabolism, and is aberrantly activated in human cancer. As such, numerous compounds targeting the PI3K pathway are currently being clinically evaluated for the treatment of cancer, and several have shown some early indications of efficacy in breast cancer. However, resistance against these agents, both de novo and acquired, may ultimately limit the efficacy of these compounds. Here, we have taken a systematic functional approach to uncovering potential mechanisms of resistance to PI3K inhibitors and have identified several genes whose expression promotes survival under conditions of PI3K/mammalian target of rapamycin (PI3K/mTOR) blockade, including the ribosomal S6 kinases RPS6KA2 (RSK3) and RPS6KA6 (RSK4). We demonstrate that overexpression of RSK3 or RSK4 supports proliferation upon PI3K inhibition both in vitro and in vivo, in part through the attenuation of the apoptotic response and upregulation of protein translation. Notably, the addition of MEK- or RSK-specific inhibitors can overcome these resistance phenotypes, both in breast cancer cell lines and patient-derived xenograft models with elevated levels of RSK activity. These observations provide a strong rationale for the combined use of RSK and PI3K pathway inhibitors to elicit favorable responses in breast cancer patients with activated RSK.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/enzimologia , Imidazóis/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Quinolinas/farmacologia , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Aminopiridinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Feminino , Expressão Gênica , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Células MCF-7 , Camundongos , Camundongos Nus , Terapia de Alvo Molecular , Morfolinas/farmacologia , Fases de Leitura Aberta , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Quinases S6 Ribossômicas 90-kDa/antagonistas & inibidores , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Transdução de Sinais , Transcriptoma , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Clin Cancer Res ; 16(9): 2688-95, 2010 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-20406840

RESUMO

PURPOSE: A subgroup of human epidermal growth factor receptor 2 (HER2)-overexpressing breast tumors coexpresses p95HER2, a truncated HER2 receptor that retains a highly functional HER2 kinase domain but lacks the extracellular domain and results in intrinsic trastuzumab resistance. We hypothesized that lapatinib, a HER2 tyrosine kinase inhibitor, would be active in these tumors. We have studied the correlation between p95HER2 expression and response to lapatinib, both in preclinical models and in the clinical setting. EXPERIMENTAL DESIGN: Two different p95HER2 animal models were used for preclinical studies. Expression of p95HER2 was analyzed in HER2-overexpressing breast primary tumors from a first-line lapatinib monotherapy study (EGF20009) and a second-line lapatinib in combination with capecitabine study (EGF100151). p95HER2 expression was correlated with overall response rate (complete + partial response), clinical benefit rate (complete response + partial response + stable disease > or =24 wk), and progression-free survival using logistic regression and Cox proportional hazard models. RESULTS: Lapatinib inhibited tumor growth and the HER2 downstream signaling of p95HER2-expressing tumors. A total of 68 and 156 tumors from studies EGF20009 and EGF100151 were evaluable, respectively, for p95HER2 detection. The percentage of p95HER2-positive patients was 20.5% in the EGF20009 study and 28.5% in the EGF100151 study. In both studies, there was no statistically significant difference in progression-free survival, clinical benefit rate, and overall response rate between p95HER2-positive and p95HER2-negative tumors. CONCLUSIONS: Lapatinib as a monotherapy or in combination with capecitabine seems to be equally effective in patients with p95HER2-positive and p95HER2-negative HER2-positive breast tumors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptores ErbB/metabolismo , Quinazolinas/uso terapêutico , Receptor ErbB-2/metabolismo , Células 3T3 , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Capecitabina , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/análogos & derivados , Humanos , Immunoblotting , Hibridização in Situ Fluorescente , Lapatinib , Neoplasias Mamárias Experimentais/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor ErbB-2/genética , Análise de Sobrevida , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Cancer Res ; 68(19): 8022-30, 2008 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-18829560

RESUMO

Phosphatidylinositol-3-kinase (PI3K) pathway deregulation is a common event in human cancer, either through inactivation of the tumor suppressor phosphatase and tensin homologue deleted from chromosome 10 or activating mutations of p110-alpha. These hotspot mutations result in oncogenic activity of the enzyme and contribute to therapeutic resistance to the anti-HER2 antibody trastuzumab. The PI3K pathway is, therefore, an attractive target for cancer therapy. We have studied NVP-BEZ235, a dual inhibitor of the PI3K and the downstream mammalian target of rapamycin (mTOR). NVP-BEZ235 inhibited the activation of the downstream effectors Akt, S6 ribosomal protein, and 4EBP1 in breast cancer cells. The antiproliferative activity of NVP-BEZ235 was superior to the allosteric selective mTOR complex inhibitor everolimus in a panel of 21 cancer cell lines of different origin and mutation status. The described Akt activation due to mTOR inhibition was prevented by higher doses of NVP-BEZ235. NVP-BEZ235 reversed the hyperactivation of the PI3K/mTOR pathway caused by the oncogenic mutations of p110-alpha, E545K, and H1047R, and inhibited the proliferation of HER2-amplified BT474 cells exogenously expressing these mutations that render them resistant to trastuzumab. In trastuzumab-resistant BT474 H1047R breast cancer xenografts, NVP-BEZ235 inhibited PI3K signaling and had potent antitumor activity. In treated animals, there was complete inhibition of PI3K signaling in the skin at pharmacologically active doses, suggesting that skin may serve as surrogate tissue for pharmacodynamic studies. In summary, NVP-BEZ235 inhibits the PI3K/mTOR axis and results in antiproliferative and antitumoral activity in cancer cells with both wild-type and mutated p110-alpha.


Assuntos
Neoplasias da Mama/genética , Proliferação de Células/efeitos dos fármacos , Imidazóis/farmacologia , Fosfatidilinositol 3-Quinases/genética , Inibidores de Fosfoinositídeo-3 Quinase , Quinolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/genética , Feminino , Humanos , Imidazóis/uso terapêutico , Camundongos , Camundongos Nus , Mutação/fisiologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Quinases/metabolismo , Quinolinas/uso terapêutico , Serina-Treonina Quinases TOR , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
8.
J Biol Chem ; 280(45): 37623-33, 2005 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-16162500

RESUMO

The MAPK signal-integrating kinases Mnk1 and Mnk2 are closely related but show marked differences in their basal activities and regulation. Both possess, within their C termini, motifs for binding to MAPKs, although these differ between Mnk1 and Mnk2. Mnk2 shows much higher activity in unstimulated cells than Mnk1, whose activity is greatly increased, e.g. by stimulation of the MEK/ERK pathway. Such increases are sensitive to blockade of that pathway, whereas the activation state of Mnk2 is relatively insensitive to inhibition of upstream signaling. Here we have studied the roles of features in their catalytic domains and C termini in determining their regulatory properties and basal activities. Mnk2 can bind to phosphorylated, active ERK, whereas Mnk1 cannot. Such binding apparently protects ERK against dephosphorylation and inactivation. The high basal activity of Mnk2 and its binding to (phospho)ERK requires features both of the catalytic domain and of the C terminus. For example, within the catalytic region an aspartate in Mnk2 plays a key role. Mutation to alanine inactivates Mnk2. In the C terminus, features within the MAPK-binding motif and to either side of it, including potential phosphorylation sites, affect MAPK binding and activity. The association of Mnks with the scaffold protein eukaryotic initiation factor 4G is negatively modulated by Mnk activity. These data indicate that multiple features determine the activities of the Mnks and thus impact on their ability to phosphorylate physiological substrates such as eukaryotic initiation factor 4E.


Assuntos
Domínio Catalítico , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Sequência de Aminoácidos , Animais , Linhagem Celular , Fator de Iniciação Eucariótico 4G/metabolismo , Flavonoides/farmacologia , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Dados de Sequência Molecular , Ligação Proteica , Proteínas Serina-Treonina Quinases/genética , Homologia de Sequência de Aminoácidos
9.
Mol Cell Biol ; 23(5): 1546-57, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12588975

RESUMO

Eukaryotic initiation factor 4E (eIF4E) binds the mRNA cap structure and forms eIF4F complexes that recruit 40S subunits to the mRNA. Formation of eIF4F is blocked by eIF4E-binding proteins such as 4E-BP1, which interacts with eIF4E via a motif in the center of its 118-residue sequence. 4E-BP1 plays key roles in cell proliferation, growth, and survival. Binding of 4E-BP1 to eIF4E is regulated by hierarchical multisite phosphorylation. Here we demonstrate that three different features in the C terminus of 4E-BP1 play distinct roles in regulating its phosphorylation and function. Firstly, we identify a new phosphorylation site in its C terminus (S101). A serine or glutamate at this position is required for efficient phosphorylation at Ser65. A second C-terminal site, S112, directly affects binding of 4E-BP1 to eIF4E without influencing phosphorylation of other sites. Thirdly, a conserved C-terminal motif influences phosphorylation of multiple residues, including rapamycin-insensitive sites. These relatively long-range effects are surprising given the reportedly unstructured nature of 4E-BP1 and may imply that phosphorylation of 4E-BP1 and/or binding to eIF4E induces a more-ordered structure. 4E-BP2 and -3 lack phosphorylatable residues corresponding to both S101 and S112. However, in 4E-BP3, replacement of the alanine at the position corresponding to S112 by serine or glutamate did not confer the ability to be released from eIF4E in response to insulin.


Assuntos
Proteínas de Transporte/química , Fosfoproteínas/química , Proteínas Adaptadoras de Transdução de Sinal , Motivos de Aminoácidos , Sequência de Aminoácidos , Sítios de Ligação , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular , Divisão Celular , Linhagem Celular , Sobrevivência Celular , Inibidores Enzimáticos/farmacologia , Fator de Iniciação 4E em Eucariotos/metabolismo , Vetores Genéticos , Ácido Glutâmico/química , Glutamina/metabolismo , Humanos , Immunoblotting , Insulina/farmacologia , Modelos Genéticos , Dados de Sequência Molecular , Mutação , Peptídeos/química , Fosfoproteínas/metabolismo , Fosforilação , Ligação Proteica , Isoformas de Proteínas , Estrutura Terciária de Proteína , Homologia de Sequência de Aminoácidos , Serina/química , Serina/metabolismo , Fatores de Tempo , Transfecção
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