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

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, 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.

Profiling of Y1 Cells Treated With FGF-2 Reveals Parallels With Oncogene-Induced Senescence

“…Acetylation at this region is typically associated with chromatin accessibility, transcriptional activation, and cell cycle progression (Zhao & Garcia, 2015). However, cells treated with FGF-2 showed a delayed accumulation of histone H4 acetylation, most notably for the di-acetylated state, at times representing the transition between G1 and S (8-12 hrs), consistent with the delayed onset of S phase after FGF-2 treatment (Dias et al, 2019). In addition to changes in acetylation on histone H4, we also observed higher levels of tri-methylation at histone H3, lysine 27 (H3K27me3) in Y1 cells treated with FGF-2 for 24 hrs (Fig.…”

“…To test this hypothesis, we treated G0-arrested Y1 cells with FBS alone or with FGF-2 and then analyzed histone PTMs at various timepoints after cell cycle progression by bottom-up mass spectrometry, which has emerged as an ideal analysis platform due to its high sensitivity, high throughput, and ability to resolve the many different types and sites of histone modifications. The timepoints chosen for analysis roughly correspond to the G1 (0.5-8 hrs), S (12-16 hrs), and G2/M (24 hrs) phases of the cell cycle based on findings with the derivative cell line Y1D1 (Dias et al, 2019). The full assortment of modifications and their relative abundances on two important regions of histone H3 (aa 27-40) and histone H4 (aa 4-17) are presented in detail in Supplemental Figs.…”

“…To examine the upstream signaling events that precede the establishment of transcriptional and epigenetic programs that contribute to senescence, we next profiled protein phosphorylation patterns using mass spectrometry. Y1 cells were serum-starved and then treated with FBS alone or FBS with FGF-2 for 5, 10, 30, or 60 mins, all of which represent timepoints that correspond to G1 phase (Dias et al, 2019). To facilitate their identification, phospho-peptides were enriched from trypsin digests using titanium dioxide beads prior to analysis by LC-MS/MS (Tables 4-7).…”

Association of PTEN Gene SNPs rs2299939 With PFS in Patients With Small Cell Lung Cancer Treated With Early Radiotherapy

“…This study predicts that five EXP genes are related to rs2299939 based on the core 15-state model. Among these genes, PAPSS2 and FGF2 are related to the DNA damage repair process (Rieswijk et al, 2015;Dias et al, 2019). PAPSS2 plays an important part in sulfate assimilation and sulfate activation, during which it exhibits both ATP sulfurylase and APS kinase activity.…”

The Rna-binding Protein GRSF1 Promote shepatocarcinogenesis via competitively Binding Toyy1 mRNA with mIR-30e-5p

“…Our results is in accordance with antitumor agent role of VE821 in other researches. Dias et al reported VE-821 could induced cancer cells death [39] . Another report also uncovered VE-821 induced BRCA1 Mutant Ovarian Cells death [40] .…”