FGFR antagonist induces protective autophagy in FGFR1-amplified breast cancer cell
Yi Chen1, Xiaoyan Xie2, Xinyi Li2
1The School of Biomedical Sciences, Chengdu Medical College, Chengdu 610083, PR China; Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, PR China.
Abstract:
Breast cancer, representing approximately 30% of all gynecological cancer cases diagnosed yearly, is a leading cause of cancer-related mortality for women. Amplification of FGFR1 is frequently observed in breast cancers and is associated with poor prognosis. Though FGFRs have long been considered as anti-cancer drug targets, and a cluster of FGFR antagonists are currently under clinical trials, the precise cellular responses under the treatment of FGFR antagonists remains unclear. Here, we show that PD166866, an FGFR1-selective inhibitor, inhibits proliferation and triggers anoikis in FGFR1-amplified breast cancer cell lines. Notably, we demonstrate that PD166866 induces autophagy in FGFR1-amplified breast cancer cell lines, while blockage of autophagy by Atg5 knockdown further enhances the anti-proliferative activities of PD166866. Moreover, mechanistic study reveals that PD166866 induces autophagy through repressing Akt/mTOR signaling pathway. Together, the present study provides new insights into the molecular mechanisms underlying the anti-tumor activities of FGFR antagonists, and may further assist the FGFRs-based drug discovery.
Insights
Fibroblast growth factor receptor 1 (FGFR1) inhibitors like PD166866 reduce breast cancer cell growth and trigger cell death. These inhibitors also induce autophagy, a cellular recycling process, which can be blocked to enhance anti-cancer effects.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Breast cancer is a leading cause of cancer mortality in women, with FGFR1 amplification linked to poor prognosis.
- Fibroblast growth factor receptors (FGFRs) are therapeutic targets, but cellular responses to their antagonists are not fully understood.
- FGFR1-selective inhibitors are being developed, necessitating research into their precise mechanisms of action.
Purpose of the Study:
- To investigate the cellular effects of PD166866, an FGFR1-selective inhibitor, on FGFR1-amplified breast cancer cells.
- To elucidate the role of autophagy in the anti-cancer activity of PD166866.
- To understand the molecular signaling pathways affected by PD166866 treatment.
Main Methods:
- Treatment of FGFR1-amplified breast cancer cell lines with PD166866.
- Assessment of cell proliferation and induction of anoikis (programmed cell death).
- Evaluation of autophagy induction and its impact on PD166866 efficacy using Atg5 knockdown.
- Mechanistic studies involving the Akt/mTOR signaling pathway.
Main Results:
- PD166866 inhibited proliferation and induced anoikis in FGFR1-amplified breast cancer cells.
- PD166866 treatment led to autophagy induction in these cell lines.
- Blocking autophagy via Atg5 knockdown potentiated the anti-proliferative effects of PD166866.
- PD166866 induced autophagy by repressing the Akt/mTOR signaling pathway.
Conclusions:
- PD166866 exhibits anti-tumor activity against FGFR1-amplified breast cancer by inhibiting proliferation and inducing anoikis and autophagy.
- Autophagy plays a complex role, with its blockage enhancing the anti-cancer efficacy of PD166866.
- The findings provide insights into the anti-tumor mechanisms of FGFR antagonists and support FGFRs-based drug discovery.
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