3 years ago

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

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

Abstract

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, sub‐lethal 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 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.

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