Increased HRD score in cisplatin resistant penile cancer cells

Background/Introduction Penile cancer is a rare disease in demand for new therapeutic options. Frequently used combination chemotherapy with 5 fluorouracil (5-FU) and cisplatin (CDDP) in patients with metastatic penile cancer mostly results in the development of acquired drug resistance. Availabilit...

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Published in:BMC cancer Vol. 22; no. 1; pp. 1352 - 14
Main Authors: Winkelmann, Ria, Bankov, Katrin, Döring, Claudia, Cinatl, Jaroslav, Grothe, Sebastian, Rothweiler, Florian, Michaelis, Martin, Schmitt, Christina, Wild, Peter J., Demes, Melanie, Cinatl, Jindrich, Vallo, Stefan
Format: Journal Article
Language:English
Published: London BioMed Central 23.12.2022
BioMed Central Ltd
BMC
Subjects:
Antineoplastic Combined Chemotherapy Protocols - pharmacology
Biomedical and Life Sciences
Biomedicine
Cancer Research
Care and treatment
Cell Line, Tumor
Cell lines
Chemoresistance
Cisplatin
Cisplatin - pharmacology
Cisplatin - therapeutic use
Development and progression
Diagnosis
Dosage and administration
Drug resistance
Drug Resistance, Neoplasm - genetics
Fluorouracil - pharmacology
Fluorouracil - therapeutic use
Health Promotion and Disease Prevention
Homologous recombination deficiency
Humans
Male
Medicine/Public Health
Oncology
Patient outcomes
Penile cancer
Penile carcinomas
Penile Neoplasms - drug therapy
Risk factors
Surgical Oncology
Germany
Penile carcinomas
Homologous recombination deficiency
Cell lines
Chemoresistance
ISSN:1471-2407, 1471-2407
Online Access:Get full text
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Summary:Background/Introduction Penile cancer is a rare disease in demand for new therapeutic options. Frequently used combination chemotherapy with 5 fluorouracil (5-FU) and cisplatin (CDDP) in patients with metastatic penile cancer mostly results in the development of acquired drug resistance. Availability of cell culture models with acquired resistance against standard therapy could help to understand molecular mechanisms underlying chemotherapy resistance and to identify candidate treatments for an efficient second line therapy. Methods We generated a cell line from a humanpapilloma virus (HPV) negative penile squamous cell carcinoma (UKF-PEC-1). This cell line was subject to chronic exposure to chemotherapy with CDDP and / or 5-FU to induce acquired resistance in the newly established chemo-resistant sublines (PEC-1 r CDDP 2500 , adapted to 2500 ng/ml CDDP; UKF-PEC-1 r 5-FU 500 , adapted to 500 ng/ml 5- FU; UKF-PEC1 r CDDP 2500 / r 5-FU 500 , adapted to 2500 ng/ml CDDP and 500 ng/ml 5 -FU). Afterwards cell line pellets were formalin-fixed, paraffin embedded and subject to sequencing as well as testing for homologous recombination deficiency (HRD). Additionally, exemplary immunohistochemical stainings for p53 and gammaH2AX were applied for verification purposes. Finally, UKF-PEC-1 r CDDP 2500 , UKF-PEC-1 r 5-FU 500 , UKF-PEC1 r CDDP 2500 / r 5-FU 500 , and UKF-PEC-3 (an alternative penis cancer cell line) were tested for sensitivity to paclitaxel, docetaxel, olaparib, and rucaparib. Results and conclusions The chemo-resistant sublines differed in their mutational landscapes. UKF-PEC-1 r CDDP 2500 was characterized by an increased HRD score, which is supposed to be associated with increased PARP inhibitor and immune checkpoint inhibitor sensitivity in cancer. However, UKF-PEC-1 r CDDP 2500 did not display sensitivity to PARP inhibitors.
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ISSN:1471-2407
1471-2407
DOI:10.1186/s12885-022-10432-7