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

cascades – including PI3K/Akt, nuclear factor kappa B (NF- Lansoprazole, traditionally used as a proton pump
κB), glucose-6-phosphate dehydrogenase (G6PD), hypoxia- inhibitor (PPI), has demonstrated potent anti-tumor effects,
inducible factor 1-alpha (HIF1α), and Notch – which govern including HDAC2 inhibition, autophagy modulation,
tumor proliferation, inflammation, and immune evasion. 56,57 and reversal of drug sequestration in acidic endosomal
Inhibition of FN3K may thus have pleiotropic effects, compartments. Its synergy with chemotherapeutic agents,
not only attenuating Nrf2’s antioxidant defense but also such as doxorubicin and metronomic cyclophosphamide
disrupting cellular metabolism, mitochondrial function, underscores its capacity to enhance intratumoral drug
and DNA repair responses through its deglycation distribution and overcome microenvironment-induced
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activity on other substrates. FN3K-sensitive proteins resistance. Importantly, lansoprazole has a wide
include ribosomal subunits, translation factors, histones, therapeutic window, favorable oral bioavailability, and a
and glycolytic enzymes, implying that FN3K may act well-established safety profile, making it a viable candidate
as a redox-modifying hub beyond Nrf2 stabilization. for combination therapies targeting the FN3K–Nrf2 axis.
Moreover, accumulation of AGEs due to reduced FN3K Collectively, the clinical readiness of these agents,
activity can activate RAGE-mediated pathways (PI3K, coupled with their distinct mechanisms of action,
MAPK, NF-κB), promoting angiogenesis, drug resistance, offers a pragmatic advantage for rapid translation. Future
and cancer progression. 3,10 trials should focus on dose-optimization, toxicity reduction
While our findings emphasize Nrf2 suppression as a through combination strategies, and patient stratification
prominent outcome of FN3K inhibition, we acknowledge the based on FN3K and Nrf2 expression to ensure precision-
possibility of off-target redox modulation. Further pathway- guided therapy in breast cancer.
mapping studies are warranted to profile global transcriptional 3.12. Statistical limitations and power
changes, ROS accumulation, and metabolic shifts induced by considerations
FN3K inhibition in tumor and normal tissues. These insights
will be crucial for identifying synergistic targets and ensuring Although the experimental results – particularly qPCR and
safety in future pre-clinical development. Western blot analyses – revealed statistically significant
downregulation of FN3K and Nrf2 across multiple breast
3.11. Translational relevance and clinical integration cancer cell lines, it is important to acknowledge that this
The repositioning of oxaliplatin, lansoprazole, and capivasertib study did not include a formal a priori power analysis.
as FN3K-targeted inhibitors necessitates careful evaluation Given the exploratory nature of the study, a fixed number
of their clinical applicability, particularly in breast cancer of biological replicates (n = 3 per group) was used, which
settings. Oxaliplatin, a third-generation platinum-based is consistent with standard practice for preliminary
chemotherapeutic, has shown efficacy beyond colorectal in vitro screening studies. Welch’s t-test was employed to
cancer, including promising results in platinum-pretreated accommodate unequal variance assumptions, and FDR
breast and ovarian cancers. Despite dose-limiting peripheral correction was applied to manage Type I errors in multiple
neuropathy, novel strategies, such as chronomodulated comparisons. However, the small sample size may reduce
delivery and calcium–magnesium infusions have been the power to detect subtle biological effects and increase
explored to mitigate toxicity. 53,58,59 Its potential in redox- the risk of false negatives (Type II errors).
sensitive tumors supports dose-sparing strategies when used Power analysis, which estimates the minimum required
in combination with targeted agents, such as FN3K inhibitors. sample size to achieve a desired statistical power (commonly
Capivasertib, a selective pan-AKT inhibitor, has been 80%) at a defined effect size and significance level (typically α
validated in hormone receptor-positive and triple-negative = 0.05), is a critical component of confirmatory pre-clinical
breast cancer (TNBC) through trials, such as CAPItello-291, studies. In this preliminary work, our objective was to
which demonstrated a significant progression-free survival identify FN3K-inhibitory candidates and assess differential
advantage when combined with fulvestrant in patients expression patterns across redox-responsive signaling
harboring PI3K/AKT/PTEN alterations. The intermittent pathways. The findings from this phase now provide the
4-days-on/3-days-off (400–480 mg BID) dosing regimen effect size estimates that will inform formal sample size
was optimized based on exposure–response modeling calculations in subsequent confirmatory studies.
to balance efficacy and tolerability, minimizing adverse Future validation studies – including in vivo tumor
events like hyperglycemia, rash, and diarrhea. These xenograft models and expanded in vitro assays with
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pharmacological characteristics support its rational dose–response replicates – will incorporate a priori power
inclusion in redox-modulatory and kinase-targeted analyses to optimize statistical robustness, minimize
regimens, including FN3K-focused strategies. sampling bias, and ensure reproducibility. This stepwise

Volume 9 Issue 3 (2025) 219 doi: 10.36922/EJMO025150114