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

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Dias, Matheus H. ; Fonseca, Cecilia S. ; Zeidler, Julianna D. ; Albuquerque, Layra L. ; da Silva, Marcelo S. ; Cararo-Lopes, Eduardo ; Reis, Marcelo S. ; Noel, Vincent ; dos Santos, Edmilson O. ; Prior, Ian A. ; Armelin, Hugo A.

• Tipo de documento: Artigo Científico
• Fonte: MOLECULAR ONCOLOGY; v. 13, n. 2, p. 17-pg., 2019-02-01.

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: 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
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - 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
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• 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
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 13/24212-7 - Bioinformática e modelagem
• Beneficiário: Vincent Olivier Jean-Marie Noel
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado