PhD Scientific Days 2023

Budapest, 22-23 June 2023

KDP Poster session

Potential role of Yes-Associated Protein 1 (YAP1) as a biomarker for anti-PD-1 resistance

Szonja Anna Kovács1,2, Balázs Győrffy1,2, Tamás Kovács3, Zoltán Varga3

1Department of Bioinformatics, Semmelweis University, Tűzoltó utca 7-9, 1094, Budapest, Hungary
2Institute of Enzymology, Research Centre for Natural Sciences, Eötvös Loránd Research Network, Magyar Tudósok körútja 2, 1117, Budapest, Hungary
3Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvárad tér 4, 1089, Budapest, Hungary

Text of the abstract

Introduction: The availability of immune-checkpoint inhibitors (ICIs) has resulted in a paradigm shift in oncology – yet the response rates fell short of expectations. To maximize the treatment benefits of immunotherapy, more robust biomarkers are needed.
Aims: Our goal was to identify predictive biomarkers of ICIs by using publicly available transcriptomic and clinical data.
Method: For statistical evaluation, Mann-Whitney U test, receiver operating characteristic analysis, and Bonferroni-correction were used.
Results: A web platform (https://rocplot.org/immune) was created with 1,434 tumor tissue samples from 19 studies for public biomarker discovery. In the pembrolizumab, or nivolumab-treated melanoma cohort (n=501), yes-associated protein 1 (YAP1, padj=3.22E-05, FC=2.21, AUC=0.725) was the best druggable candidate overexpressed in non-responding patients. Other promising candidates were spindlin 1 (SPIN1, padj=4.83E-05, FC=1.70, AUC=0.721), plastin 3 (PLS3, padj=1.61E-04, FC=1.80, AUC=0.709), Ras homolog family member Q (RHOQ, padj=2.77E-04, FC=1.74, AUC=0.701), and potassium channel tetramerization domain containing 15 (KCTD, padj=1.29E-05, FC=2.03, AUC=0.729). To study the effects of pharmacological inhibition of YAP1, C57BL/6J mice are being inoculated with melanoma cell lines (B16-F10, B16-OVA MO4, YUMM1.7, and YUMMER1.7), and a gene panel is validated on formalin-fixed, paraffin-embedded (FFPE) samples from melanoma patients.
Conclusion: A database was set up for the discovery of ICI biomarkers, and a gene panel was chosen for ex vivo validation. Animal models of immunologically “hot” and “cold” tumors were optimized for testing the effects of YAP1 inhibition. All experiments were approved by the National Scientific Ethical Committee on Animal Experimentation in Hungary (license no. PE/EA/01017-6/2022), and the National Public Health Center (35314-7/2021/EÜIG).
Funding: PharmaLab, RRF-2.3.1-21-2022-00015, TKP-2021-NVA-15, and 2020-1.1.6-JÖVŐ-2021-00013, KDP-2020.