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1.
Nature ; 518(7538): 240-4, 2015 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-25409150

RESUMO

Broad and deep tumour genome sequencing has shed new light on tumour heterogeneity and provided important insights into the evolution of metastases arising from different clones. There is an additional layer of complexity, in that tumour evolution may be influenced by selective pressure provided by therapy, in a similar fashion to that occurring in infectious diseases. Here we studied tumour genomic evolution in a patient (index patient) with metastatic breast cancer bearing an activating PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha, PI(3)Kα) mutation. The patient was treated with the PI(3)Kα inhibitor BYL719, which achieved a lasting clinical response, but the patient eventually became resistant to this drug (emergence of lung metastases) and died shortly thereafter. A rapid autopsy was performed and material from a total of 14 metastatic sites was collected and sequenced. All metastatic lesions, when compared to the pre-treatment tumour, had a copy loss of PTEN (phosphatase and tensin homolog) and those lesions that became refractory to BYL719 had additional and different PTEN genetic alterations, resulting in the loss of PTEN expression. To put these results in context, we examined six other patients also treated with BYL719. Acquired bi-allelic loss of PTEN was found in one of these patients, whereas in two others PIK3CA mutations present in the primary tumour were no longer detected at the time of progression. To characterize our findings functionally, we examined the effects of PTEN knockdown in several preclinical models (both in cell lines intrinsically sensitive to BYL719 and in PTEN-null xenografts derived from our index patient), which we found resulted in resistance to BYL719, whereas simultaneous PI(3)K p110ß blockade reverted this resistance phenotype. We conclude that parallel genetic evolution of separate metastatic sites with different PTEN genomic alterations leads to a convergent PTEN-null phenotype resistant to PI(3)Kα inhibition.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos/genética , PTEN Fosfo-Hidrolase/deficiência , PTEN Fosfo-Hidrolase/genética , Inibidores de Fosfoinositídeo-3 Quinase , Tiazóis/farmacologia , Alelos , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Classe I de Fosfatidilinositol 3-Quinases , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Perda de Heterozigosidade/efeitos dos fármacos , Perda de Heterozigosidade/genética , Camundongos , Camundongos Nus , PTEN Fosfo-Hidrolase/metabolismo , Tiazóis/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Science ; 346(6216): 1480-6, 2014 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-25394791

RESUMO

Targeted cancer therapies have produced substantial clinical responses, but most tumors develop resistance to these drugs. Here, we describe a pharmacogenomic platform that facilitates rapid discovery of drug combinations that can overcome resistance. We established cell culture models derived from biopsy samples of lung cancer patients whose disease had progressed while on treatment with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors and then subjected these cells to genetic analyses and a pharmacological screen. Multiple effective drug combinations were identified. For example, the combination of ALK and MAPK kinase (MEK) inhibitors was active in an ALK-positive resistant tumor that had developed a MAP2K1 activating mutation, and the combination of EGFR and fibroblast growth factor receptor (FGFR) inhibitors was active in an EGFR mutant resistant cancer with a mutation in FGFR3. Combined ALK and SRC (pp60c-src) inhibition was effective in several ALK-driven patient-derived models, a result not predicted by genetic analysis alone. With further refinements, this strategy could help direct therapeutic choices for individual patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Modelagem Computacional Específica para o Paciente , Inibidores de Proteínas Quinases/uso terapêutico , Quinase do Linfoma Anaplásico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/genética , Análise Mutacional de DNA , Ensaios de Seleção de Medicamentos Antitumorais , Ativação Enzimática/genética , Receptores ErbB/antagonistas & inibidores , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , MAP Quinase Quinase 1/genética , MAP Quinase Quinase 1/metabolismo , Mutação , Proteínas Proto-Oncogênicas pp60(c-src)/antagonistas & inibidores , Pirimidinas/uso terapêutico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Sulfonas/uso terapêutico , Células Tumorais Cultivadas
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