PhD Scientific Days 2026

Poster Session 2.E - Pathological and Oncological Sciences

The Relationship Between Hypoxia and the Development of Therapy Resistance in Solid Tumors

Name of the presenter

Juhász, Ákos

Institute/workplace of the presenter

National Institute of Oncology

Authors

Ákos Juhász¹, Mátyás Selmeci¹, Andrea Ladányi¹, József Tóvári¹, Tamás Mihály Cserepes¹
1: National Institute of Oncology

Text of the abstract

Introduction
We investigated the development of drug resistance to tyrosine kinase inhibitors (TKIs) in melanoma and renal cell carcinoma (RCC) tumor samples. In melanoma, the BRAF inhibitor vemurafenib was combined with inhibition of the ABCB1 effect, previously identified by our group. In metastatic RCC (mRCC), the multikinase inhibitor sunitinib was studied in combination with HIF inhibitors due to the high prevalence of VHL mutations in RCC.
Aims
Our goal was to identify combinations of active compounds capable of preventing or reversing the development of resistance. In preclinical model systems, we utilized both the reproducibility of cell line experiments and the clinical relevance of patient-derived tumor xenograft (PDX) models.
Methods
In vitro experiments were conducted on two melanoma cell lines (A375, SK-MEL-28), testing the combination of vemurafenib and the ABCB1 inhibitor (tariquidar).
In three VHL wild-type (Caki-1, SN-12C, UO-31) and two VHL-mutant (A498, 786-O) RCC cell lines, MTT proliferation assays were used to determine the IC₅₀ values of sunitinib and HIF inhibitors (acriflavine, PX478, and vorinostat). Additionally, changes in sunitinib sensitivity were examined in the presence of subtoxic concentrations of HIF inhibitors.
The long-term effects of sunitinib treatment were investigated in two VHL wild-type RCC PDX models. In two VHL-mutant PDX models, as well as in the 786-O xenograft model, the combination of sunitinib and acriflavine was examined.
For both PDX and cell line experiments, genomic (mRNA-seq) analyses were performed to identify potential resistance mechanisms.
Results
In RCC, in vitro tests showed additive effects for acriflavine and vorinostat, while PX478 exhibited a mild sensitizing (synergistic) effect. In vivo, the combination of acriflavine and sunitinib proved to be more effective than monotherapy.
Analysis of mRNA sequencing data from resistant cell lines and PDX models identified genes involved in resistance related not only to hypoxia signaling but also to xenobiotic metabolism, TNFα signaling, and glycolysis. Proteomic validation of these findings is currently underway.
Conclusion
The therapy-resistant cell lines and PDX models we developed, revealed mechanisms of resistance to targeted therapies. The success of the sunitinib–acriflavine combination is supported by our animal experiments.
Funding
2025-2.1.2-EKÖP-KDP