Expression of p53 protein associates with anti-pd-l1 treatment response on human-derived xenograft model of gata3/cr5/6-negative recurrent nonmuscular invasive bladder urothelial carcinoma

Background: The possible involvement of p53 signaling, FGFR3 expression, and FGFR3 mutation rates in the prediction of the NMIBC anti-PD-L1 treatment response needs to be clarified. The main aim of our study was to explore predictive value of p53 expression, FGFR3 expression, and its gene mutation status for the therapeutic success of anti-PD-L1 treatment in the patient-derived murine model of recurrent high-PD-L1(+) GATA3(-)/CR5/6(-) high-grade and low-grade NMIBC. Methods: twenty lines of patient-derived xenografts (PDXs) of relapsed high-PD-L1(+) double-negative NMIBC were developed, of which 10 lines represented high-grade tumors and the other ones—low-grade bladder cancer. Acceptors of each grade-related branch received specific anti-PD-L1 antibodies. Animals’ survival, tumor-doubling time, and remote metastasis were followed during the post-interventional period. PD-L1, GATA3, CR5/6, and p53 protein expressions in engrafted tumors were assessed by immunohistochemistry. The FGFR3 expression and FGFR3 mutations in codons 248 and 249 were detected by real-time polymerase chain reaction. Results: The expression of p53 protein is an independent factor affecting the animals’ survival time [HR = 0.036, p = 0.031] of anti-PD-L1-treated mice with low-grade high-PD-L1(+) double-negative NMIBC PDX. The FGFR3 expression and FGFR3 mutation rate have no impact on the anti-PD-L1 treatment response in the interventional groups. Conclusions: p53 expression may be considered as a prognostic factor for the anti-PD-L1 treatment efficacy of low-grade high-PD-L1-positive GATA3(-)/CR5/6(-)relapsed noninvasive bladder cancer. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Blinova E.1, 2 , Samishina E.3 , Deryabina O.4 , Blinov D.3, 5 , Roshchin D.6 , Shich E.1 , Tumutolova O.4 , Fedoseykin I.1 , Epishkina A.1 , Barakat H. 7 , Kaprin A. 6 , Zhandarov K.1 , Perepechin D.6 , Merinov D.6 , Brykin G.1 , Arutiunian K.8 , Serebrianyi S.6 , Mirontsev A.1 , Kozdoba A.8
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  • 1 Department of Clinical Anatomy and Operative Surgery, Department of Pharmacology and Pharmaceutic Technology, Sechenov University, 8/1 Trubetzkaya Street, Moscow, 119991, Russian Federation
  • 2 Department of Fundamental Medicine, National Research Nuclear University MEPHI, 31, Kashirskoe Highway, Moscow, 115409, Russian Federation
  • 3 Laboratory of Molecular Pharmacology and Drug Design, Department of Pharmaceutical Chemistry, All-Union Research Center for Biological Active Compounds Safety, 23 Kirova Street, Staraja Kupavna, 142450, Russian Federation
  • 4 Department of Pathology, Laboratory of Pharmacology, National Research Ogarev Mordovia State University, 68 Bolshevistskaya Street, Saransk, 430005, Russian Federation
  • 5 Laboratory of Molecular Pharmacology, Department of Clinical Trials and Scientific Research, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, 1 Samory Mashela Street, Moscow, 117997, Russian Federation
  • 6 Department of Oncological Urology, Russian National Research Medical Center of Radiology, Botkinsky Proezd, Moscow, 125284, Russian Federation
  • 7 Российский университет дружбы народов
  • 8 Department of Urology, Andrology and Oncology, Pirogov Russian National Research Medical University, 1 Ostrovityanova Street, Moscow, 117997, Russian Federation
Ключевые слова
Anti-PD-L1 therapy; Double-negative molecular subtype; FGFR3 expression; FGFR3 mutations; Human-derived xenograft model; Mice; Nonmuscular invasive bladder cancer; P53 expression; Response
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