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1.
Oncology (Williston Park) ; 32(4): 156-63, 2018 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-29684234

RESUMO

Brain metastases are common in patients with non-small-cell lung cancer (NSCLC). Because of associated poor prognosis and limited specific treatment options, there is a real need for the development of medical therapies and strategies for affected patients. Novel compounds for epidermal growth factor receptor-dependent and anaplastic lymphoma kinase-dependent lung cancer have demonstrated blood-brain barrier permeability and have led to important improvements in central nervous system outcomes. Studies of targeted therapies for oncogene-driven tumors and of immunotherapies in patients with brain metastases have shown promise and, allied with novel radiation techniques, are driving a rapid evolution in treatment and prognosis for NSCLC brain metastases.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/secundário , Neoplasias Pulmonares/patologia , Quinase do Linfoma Anaplásico , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Humanos , Imunoterapia , Mutação , Receptores Proteína Tirosina Quinases/antagonistas & inibidores
2.
Cancer Res ; 79(4): 689-698, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30718357

RESUMO

EGFR-activating mutations are observed in approximately 15% to 20% of patients with non-small cell lung cancer. Tyrosine kinase inhibitors have provided an illustrative example of the successes in targeting oncogene addiction in cancer and the role of tumor-specific adaptations conferring therapeutic resistance. The compound osimertinib is a third-generation tyrosine kinase inhibitor, which was granted full FDA approval in March 2017 based on targeting EGFR T790M resistance. The compound has received additional FDA approval as first-line therapy with improvement in progression-free survival by suppressing the activating mutation and preventing the rise of the dominant resistance clone. Drug development has been breathtaking in this space with other third-generation compounds at various stages of development: rociletinib (CO-1686), olmutinib (HM61713), nazartinib (EGF816), naquotinib (ASP8273), mavelertinib (PF-0647775), and AC0010. However, therapeutic resistance after the administration of third-generation inhibitors is complex and not fully understood, with significant intertumoral and intratumoral heterogeneity. Repeat tissue and plasma analyses on therapy have revealed insights into multiple mechanisms of resistance, including novel second site EGFR mutations, activated bypass pathways such as MET amplification, HER2 amplification, RAS mutations, BRAF mutations, PIK3CA mutations, and novel fusion events. Strategies to understand and predict patterns of mutagenesis are still in their infancy; however, technologies to understand synthetically lethal dependencies and track cancer evolution through therapy are being explored. The expansion of combinatorial therapies is a direction forward targeting minimal residual disease and bypass pathways early based on projected resistance.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Humanos , Neoplasias Pulmonares/patologia , Prognóstico
3.
Hematol Oncol Clin North Am ; 31(1): 113-129, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27912827

RESUMO

With the implementation of genomic technologies into clinical practice, we have examples of the predictive benefit of targeted therapy for oncogene-addicted cancer and identified molecular dependencies in non-small cell lung cancer. The clinical success of tyrosine kinase inhibitors against epidermal growth factor receptor and anaplastic lymphoma kinase activation has shifted treatment emphasize the separation of subsets of lung cancer and genotype-directed therapy. Advances have validated oncogenic driver genes and led to the development of targeted agents. This review highlights treatment options, including clinical trials for ROS1 rearrangement, RET fusions, NTRK1 fusions, MET exon skipping, BRAF mutations, and KRAS mutations.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas , Sistemas de Liberação de Medicamentos/métodos , Neoplasias Pulmonares , Mutação , Proteínas de Neoplasias , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo
4.
Mol Cancer Ther ; 16(2): 265-272, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28159915

RESUMO

The vast majority of patients with metastatic lung cancers who initially benefit from EGFR-targeted therapies eventually develop resistance. An increasing understanding of the number and complexity of resistance mechanisms highlights the challenge of treating tumors resistant to EGFR inhibitors. Resistance mechanisms include new, second-site mutations within EGFR (e.g., T790M and C797S), upregulation of MET kinase, upregulation of insulin growth factor receptor (IGFR), HER2 amplification, increased expression of AXL, BIM modulation, NF-κB activation, histologic switch to small-cell cancer, epithelial-to-mesenchymal transition, PDL1 expression with subsequent immune tolerance, and release of cytokines such as TGFß and IL6. Herein, we review the growing body of knowledge regarding EGFR bypass pathways, and the development of new drugs and combination treatment strategies to overcome resistance. Mol Cancer Ther; 16(2); 265-72. ©2017 AACR.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/farmacologia , Animais , Antineoplásicos/uso terapêutico , Biomarcadores , Proteínas de Transporte , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/metabolismo , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Terapia de Alvo Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral
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