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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Fibroblast Growth Factor 2 lethally sensitizes cancer cells to stress-targeted therapeutic inhibitors

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Autor(es):
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Dias, Matheus H. [1, 2, 3] ; Fonseca, Cecilia S. [4, 1, 2] ; Zeidler, Julianna D. [1, 2] ; Albuquerque, Layra L. [1, 2] ; da Silva, Marcelo S. [1, 2] ; Cararo-Lopes, Eduardo [4, 1, 2] ; Reis, Marcelo S. [1, 2] ; Noel, Vincent [1, 2] ; dos Santos, Edmilson O. [1, 2] ; Prior, Ian A. [3] ; Armelin, Hugo A. [4, 1, 2]
Número total de Autores: 11
Afiliação do(s) autor(es):
[1] Ctr Toxins Immune Response & Cell Signaling CeTIC, Sao Paulo - Brazil
[2] Inst Butantan, LECC, Sao Paulo - Brazil
[3] Univ Liverpool, Inst Translat Med, Cellular & Mol Physiol, Liverpool, Merseyside - England
[4] Univ Sao Paulo, Inst Quim, Sao Paulo - Brazil
Número total de Afiliações: 4
Tipo de documento: Artigo Científico
Fonte: MOLECULAR ONCOLOGY; v. 13, n. 2, p. 290-306, FEB 2019.
Citações Web of Science: 0
Resumo

In malignant transformation, cellular stress-response pathways are dynamically mobilized to counterbalance oncogenic activity, keeping cancer cells viable. Therapeutic disruption of this vulnerable homeostasis might change the outcome of many human cancers, particularly those for which no effective therapy is available. Here, we report the use of fibroblast growth factor 2 (FGF2) to demonstrate that further mitogenic activation disrupts cellular homeostasis and strongly sensitizes cancer cells to stress-targeted therapeutic inhibitors. We show that FGF2 enhanced replication and proteotoxic stresses in a K-Ras-driven murine cancer cell model, and combinations of FGF2 and proteasome or DNA damage response-checkpoint inhibitors triggered cell death. CRISPR/Cas9-mediated K-Ras depletion suppressed the malignant phenotype and prevented these synergic toxicities in these murine cells. Moreover, in a panel of human Ewing's sarcoma family tumor cells, sublethal concentrations of bortezomib (proteasome inhibitor) or VE-821 (ATR inhibitor) induced cell death when combined with FGF2. Sustained MAPK-ERK1/2 overactivation induced by FGF2 appears to underlie these synthetic lethalities, as late pharmacological inhibition of this pathway restored cell homeostasis and prevented these described synergies. Our results highlight how mitotic signaling pathways which are frequently overridden in malignant transformation might be exploited to disrupt the robustness of cancer cells, ultimately sensitizing them to stress-targeted therapies. This approach provides a new therapeutic rationale for human cancers, with important implications for tumors still lacking effective treatment, and for those that frequently relapse after treatment with available therapies. (AU)

Processo FAPESP: 12/20186-9 - Mecanismos moleculares da interação funcional entre Ras e ciclina D1 em células malignas dependentes de Ras
Beneficiário:Matheus Henrique dos Santos Dias
Linha de fomento: Bolsas no Brasil - Pós-Doutorado
Processo FAPESP: 13/09040-5 - Investigação dos mecanismos moleculares envolvidos no bloqueio da transição G2- mitose induzido por FGF2 em células malignas dependentes de Ras
Beneficiário:Cecilia Sella Fonseca
Linha de fomento: Bolsas no Brasil - Doutorado Direto
Processo FAPESP: 13/24212-7 - Bioinformática e modelagem
Beneficiário:Vincent Olivier Jean-Marie Noel
Linha de fomento: Bolsas no Brasil - Pós-Doutorado
Processo FAPESP: 16/17945-6 - Investigação das redes proteômicas e fosfoproteômicas envolvidas na atividade complementar de ciclina D1 para a transformação maligna por Ras
Beneficiário:Matheus Henrique dos Santos Dias
Linha de fomento: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado