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

Autor: Dias MH; Center of Toxins, Immune-response and Cell Signaling (CeTICS) and Laboratório Especial de Ciclo Celular (LECC), Instituto Butantan, São Paulo, Brazil.; Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, UK., Fonseca CS; Center of Toxins, Immune-response and Cell Signaling (CeTICS) and Laboratório Especial de Ciclo Celular (LECC), Instituto Butantan, São Paulo, Brazil.; Instituto de Química, Universidade de São Paulo, Brazil., Zeidler JD; Center of Toxins, Immune-response and Cell Signaling (CeTICS) and Laboratório Especial de Ciclo Celular (LECC), Instituto Butantan, São Paulo, Brazil., Albuquerque LL; Center of Toxins, Immune-response and Cell Signaling (CeTICS) and Laboratório Especial de Ciclo Celular (LECC), Instituto Butantan, São Paulo, Brazil., da Silva MS; Center of Toxins, Immune-response and Cell Signaling (CeTICS) and Laboratório Especial de Ciclo Celular (LECC), Instituto Butantan, São Paulo, Brazil., Cararo-Lopes E; Center of Toxins, Immune-response and Cell Signaling (CeTICS) and Laboratório Especial de Ciclo Celular (LECC), Instituto Butantan, São Paulo, Brazil.; Instituto de Química, Universidade de São Paulo, Brazil., Reis MS; Center of Toxins, Immune-response and Cell Signaling (CeTICS) and Laboratório Especial de Ciclo Celular (LECC), Instituto Butantan, São Paulo, Brazil., Noël V; Center of Toxins, Immune-response and Cell Signaling (CeTICS) and Laboratório Especial de Ciclo Celular (LECC), Instituto Butantan, São Paulo, Brazil., Dos Santos EO; Center of Toxins, Immune-response and Cell Signaling (CeTICS) and Laboratório Especial de Ciclo Celular (LECC), Instituto Butantan, São Paulo, Brazil., Prior IA; Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, UK., Armelin HA; Center of Toxins, Immune-response and Cell Signaling (CeTICS) and Laboratório Especial de Ciclo Celular (LECC), Instituto Butantan, São Paulo, Brazil.; Instituto de Química, Universidade de São Paulo, Brazil.
Jazyk: angličtina
Zdroj: Molecular oncology [Mol Oncol] 2019 Feb; Vol. 13 (2), pp. 290-306. Date of Electronic Publication: 2018 Dec 03.
DOI: 10.1002/1878-0261.12402
Abstrakt: 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.
(© 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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