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Eurasian Journal of
Medicine and Oncology FN3K–Nrf2 axis inhibition in breast cancer

for breast cancer. However, several critical avenues remain and capivasertib – that significantly inhibited FN3K
to be explored to fully establish its clinical relevance. First, expression and function. This inhibition was corresponded
while the study establishes the inhibitory effects of selected with suppression of Nrf2-mediated antioxidant signaling
FN3K inhibitors on breast cancer cell lines, further in-depth and reduced cancer cell viability, supporting the role of
mechanistic investigations are required to elucidate the FN3K in tumor progression and redox adaptation.
precise molecular role of FN3K in cancer progression. Importantly, all three compounds demonstrated
These should include studies on FN3K-mediated metabolic strong selectivity toward breast cancer cells with minimal
adaptations and its impact on oxidative stress pathways
beyond Nrf2 signaling; as such investigations would cytotoxicity in normal cells, indicating a favorable
provide deeper insights into its therapeutic potential. therapeutic index. These findings collectively support the
Secondly, in vivo studies and pharmacokinetics are FN3K–Nrf2 axis as a promising molecular target in redox-
critical; although initial in vivo validation demonstrated driven breast cancer subtypes.
significant tumor growth suppression, comprehensive While the present findings are encouraging, we
pharmacokinetic and toxicological evaluations in animal acknowledge the limitation that in vivo validation was not
models are essential. Determining the bioavailability, included in this phase of the study. To address this, future
metabolic stability, and potential off-target effects of FN3K experiments are already planned to assess the efficacy and
inhibitors will be crucial before progressing to clinical safety of FN3K inhibition in xenograft tumor models.
trials. In addition, the development of selective FN3K These will include evaluation of tumor growth suppression,
inhibitors from existing FDA-approved drugs, future pharmacokinetic profiles, and modulation of the FN3K–
efforts should focus on rational drug design to develop Nrf2 axis in excised tumor tissues. In addition, downstream
more selective inhibitors with minimal off-target effects. molecular pathway mapping, ADME optimization, and
Computational approaches, such as MD simulations and combinatorial strategies with standard therapeutics will be
free energy perturbation studies can aid in optimizing explored to facilitate translational relevance.
lead compounds for enhanced specificity and efficacy.
Furthermore, exploration of combination therapies is Overall, this work establishes FN3K inhibition
warranted. Given the role of FN3K in modulating oxidative as a viable therapeutic strategy for breast cancer and
stress responses, investigating its inhibition in combination provides a strong foundation for future in vivo and
with chemotherapeutic agents or targeted therapies could clinical investigations. Based on the present stage of
provide synergistic effects. Evaluating the impact of FN3K validation, oxaliplatin, lansoprazole, and capivasertib
inhibitors on drug resistance mechanisms may reveal novel should be regarded as promising pre-clinical candidates
combination strategies to enhance treatment efficacy. For for FN3K-targeted intervention, rather than as definitive
clinical translation and biomarker development, studies therapeutic options. Further in vivo and combination
should assess FN3K expression patterns in patient-derived therapy studies are required to fully determine their
tumor samples and correlate them with disease progression clinical applicability.
and treatment response. Identifying reliable biomarkers
associated with FN3K inhibition will be instrumental in Acknowledgments
patient stratification and personalized therapy approaches. The authors acknowledge the JSS Academy of Higher
Finally, CRISPR/Cas9-based gene editing approaches, Education and Research and the JSS College of Pharmacy
including knockout or knockdown studies in breast cancer for providing institutional support. The Department of
models, can help validate the direct contribution of FN3K Computer Aided Drug Design is gratefully acknowledged
to tumorigenesis. Functional studies in FN3K-deficient for providing the computational resources essential for
models will clarify its essentiality in breast cancer survival the in silico studies. The authors also express their sincere
and progression. thanks to Dr. Subramanyam P, Muppandal Genomics and
By addressing these critical aspects, FN3K-targeted Immunologicals Pvt. Ltd., Hyderabad, for his technical
therapy can move closer to clinical application, offering a assistance in conducting the in vitro biological experiments
promising avenue for breast cancer treatment. and supporting data validation.
6. Conclusion Funding

The present study underscores the therapeutic potential The work was supported by the Council of Scientific and
of targeting FN3K in breast cancer management. By Industrial Research, Human Resource Development
integrating in silico virtual screening with in vitro validation, Group (CSIR-HRDG), New Delhi, India (Grant No.111-
we identified lead compounds – oxaliplatin, lansoprazole, 5634- 11759/2023/1 dated February 19 , 2024).
th

Volume 9 Issue 3 (2025) 221 doi: 10.36922/EJMO025150114