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Essential role of AKT in tumor cells addicted to FGFR
Yi Hu1, Huiru Lu, Jinchao Zhang
1aCAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Key Laboratory of Nuclear Analytical Techniques, Institute of High Energy Physics, Chinese Academy of Sciences (CAS) bDepartment of Medicinal Chemistry, Chinese Academy of Medical Sciences, Beijing cKey Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Environmental Science, Hebei University, Baoding, China.
Abstract:
Tumor cells with genetic amplifications or mutations in the fibroblast growth factor receptor (FGFR) family are often addicted to FGFR and heavily dependent on its signaling to survive. Although it is critical to understand which signaling pathway downstream of FGFR plays an essential role to guide the research and development of FGFR inhibitors, it has remained unclear partly because the tool compounds used in the literature also hit many other kinases, making the results difficult to interpret. With the development of a potent FGFR-specific inhibitor, BGJ398, we are now able to dissect various pathways with low drug concentrations to minimize multiple-target effects. Importantly, here, we show that inhibition of FGFR signaling by BGJ398 leads to only transient inhibition of ERK1/2 phosphorylation, whereas the inhibitory effect on AKT phosphorylation is sustainable, indicating that AKT, not ERK as commonly believed, serves as an appropriate pharmacodynamic biomarker for BGJ398. Although AKT inhibition by a pan-PI3K inhibitor alone has almost no effect on cell growth, heterologous expression of myr-AKT, an active form of AKT, rescues BGJ398-mediated suppression of tumor cell proliferation. These results indicate that AKT is an essential component downstream of FGFR. Finally, combination of the FGFR inhibitor BGJ398 with rapamycin significantly inhibits AKT phosphorylation and enhances their antiproliferative effects in FGFR-addicted cells, suggesting an effective combination strategy for clinical development of FGFR inhibitors.
Insights
Fibroblast growth factor receptor (FGFR) inhibitors like BGJ398 target AKT, not ERK, for sustained tumor cell growth suppression. Combining FGFR inhibitors with rapamycin shows promise for effective cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Tumor cells with genetic alterations in fibroblast growth factor receptor (FGFR) signaling pathways are highly dependent on this pathway for survival.
- Previous studies on FGFR inhibitors were limited by off-target effects of tool compounds, hindering the identification of critical downstream signaling pathways.
Purpose of the Study:
- To identify the key downstream signaling pathway regulated by FGFR addiction in tumor cells.
- To establish a reliable pharmacodynamic biomarker for FGFR inhibitors.
- To explore effective combination strategies for FGFR inhibitor-based cancer therapy.
Main Methods:
- Utilized BGJ398, a potent and specific FGFR inhibitor, at low concentrations to minimize off-target effects.
- Assessed the phosphorylation status of downstream signaling molecules, including ERK1/2 and AKT.
- Investigated the role of AKT in FGFR-mediated tumor cell proliferation using myr-AKT expression and combination therapy with rapamycin.
Main Results:
- BGJ398 treatment resulted in transient ERK1/2 phosphorylation inhibition but sustained AKT phosphorylation inhibition.
- AKT was identified as a crucial downstream mediator of FGFR signaling, essential for tumor cell proliferation.
- Combination therapy of BGJ398 with rapamycin demonstrated enhanced inhibition of AKT phosphorylation and significant antiproliferative effects in FGFR-addicted cells.
Conclusions:
- Sustained AKT inhibition, not ERK inhibition, is a reliable pharmacodynamic biomarker for FGFR inhibitors like BGJ398.
- AKT signaling is essential for the proliferation of tumor cells dependent on FGFR signaling.
- Combination of FGFR inhibitors with rapamycin presents a promising therapeutic strategy for FGFR-driven cancers.
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