roblitinib (FGF401)

The FGF401/everolimus combination effectively suppressed tumor cell proliferation; promoted apoptosis; reduced tumor hypoxia via blood vessel normalization; and downregulated key proteins involved in proliferation, survival, metastasis, and angiogenesis. These preclinical findings provide a strong rationale for clinical trials combining FGFR4 and mTOR inhibitors in HCC patients with FGF19/FGFR4/mTOR-dependent tumors.

We identify leucine usage as a key factor driving the growth of aggressive PAX-fusion tumors, as limiting its bioavailability impaired oxidative phosphorylation and mitochondrial metabolism, delaying tumor progression and improving survival in vivo. Our data provide a compelling list of actionable targets and suggest promising new strategies to treat this tumor.

Our data showed that a selective inhibitor of FGFR4, FGF401, can improve the therapeutic efficacy of carboplatin in a xenograft mouse model of ovarian cancer. This study has demonstrated the therapeutic potential of targeting the SORL1/FGFR4 pathway to improve the chemoresponse of patients with recurrent and/or resistant ovarian cancer.

We believe that FGFR4 overexpression and complex formation with HER2 can serve as molecular markers to assist clinicians in identifying trastuzumab-resistant tumors. Our results suggest that FGF401 combined with trastuzumab as adjuvant therapy for patients with trastuzumab-resistant breast cancer may be a potential new treatment strategy.

For instance, roblitinib induces ferroptosis of trastuzumab-resistant human epidermal growth factor receptor 2 (HER2)-positive breast cancer cells by diminishing fibroblast growth factor receptor 4 (FGFR4) expression, thereby augmenting the susceptibility of these cells to HER2-targeted therapies. In tamoxifen-resistant breast cancer cells, Fascin exacerbates their resistance by repressing solute carrier family 7 member 11 (SLC7A11) expression, which in turn heightens their responsiveness to tamoxifen. In recent years, Chinese herbs extracts and therapeutic drugs have been demonstrated to elicit ferroptosis in breast cancer cells by modulating a spectrum of regulatory factors pertinent to ferroptosis, including SLC7A11, glutathione peroxidase 4 (GPX4), acyl-CoA synthetase long chain family member 4 (ACSL4), and heme oxygenase 1 (HO-1). Here, we review the roles and mechanisms of Chinese herbal extracts and therapeutic drugs in regulating ferroptosis in breast cancer, providing potential therapeutic options for anti-breast cancer.

Together these data unreveal a previously unregnized regulatory mechanism of FGFR4 by LIF/LIFR and demonstrate that LIF and FGF19 converge on the regulation of oncogenic STAT3 in GC cells.

Collectively, our study highlighted the potential of the therapeutic combination of FGFR4 and EZH2 inhibitors, which would provide new references for the further development of clinical treatment strategies for HCC.

Eighty milligrams BID was the MTD and RP2D for EVER4010001 plus pembrolizumab. Efficacy results were promising, and no new safety risks were reported, justifying the Phase 2 portion of this study.

Our results pave the way for precision medicine approaches against FGFR4 V550L-driven RMS.

The final PK/PD model was used to simulate effect of patients' characteristics on tumor growth inhibition profiles. The proposed methodology can be used to support drug development decisions, especially when large interpatient variability is observed.

At biologically active doses, FGF401 alone or combined with spartalizumab was safe in patients with FGFR4/KLB-positive tumors including HCC. Preliminary clinical efficacy was observed. Further clinical evaluation of FGF401 using a refined biomarker strategy is warranted.