TY  - JOUR
T1  - Synergistic Inhibition of Hepatocellular Carcinoma Growth via Combined mTOR Blockade and Microtubule Disruption
A1  - Maria Gonzalez
A1  - Javier Ruiz
A1  - Lucia Torres
A1  - Elena Ruiz
JF  - Bulletin of Pioneering Researches of Medical and Clinical Science
JO  - Bull Pioneer Res Med Clin Sci
SN  - 3006-2659
Y1  - 2025
VL  - 5
IS  - 1
DO  - 10.51847/3W32MQtXb8
SP  - 242
EP  - 259
N2  - Hepatocellular carcinoma (HCC) poses considerable therapeutic challenges, given that standard chemotherapies offer only restricted benefit. The mammalian target of rapamycin/sirolimus (mTOR) and microtubules represent two major druggable vulnerabilities in HCC. In this work, we demonstrated that concurrent mTOR inhibition with mTOR inhibitors (everolimus and sirolimus) and the microtubule inhibitor vinorelbine yielded outcomes superior to those of single-agent regimens in HCC PDX models. Our data indicate that vinorelbine halts cells in mitosis, promotes apoptosis, and restores a more normal vascular architecture within tumors, while simultaneously increasing survivin levels and activating the mTOR/p70S6K/4EBP1 signaling axis. Supplementing treatment with everolimus substantially augmented tumor sensitivity to vinorelbine, translating into extended overall survival (OS) across the majority of orthotopic HCC PDX models examined. Mechanistic dissection revealed that this pronounced tumor-suppressive effect correlated with diminished expression of mTOR effectors (p-p70S6K, p-4EBP1, and p-S6K), several pivotal cell-cycle regulatory proteins, and the anti-apoptotic factor survivin. Importantly, these molecular changes did not disrupt the vascular normalization elicited by vinorelbine in vinorelbine-responsive PDX models or by everolimus in everolimus-responsive PDX models. The pairing of everolimus with vinorelbine (everolimus/vinorelbine) also fostered apoptosis while exhibiting minimal toxicity. Given the affordability and documented clinical activity of everolimus and notably sirolimus, this combination strategy warrants further assessment in early-stage clinical trials.
UR  - https://bprmcs.com/article/synergistic-inhibition-of-hepatocellular-carcinoma-growth-via-combined-mtor-blockade-and-microtubule-u7ozpdd9ronmsfg
ER  -