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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Veröffentlicht in:	BMC cancer Jg. 22; H. 1; S. 1352 - 14
Hauptverfasser:	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
Sprache:	Englisch
Veröffentlicht:	London BioMed Central 23.12.2022 BioMed Central Ltd BMC
Schlagworte:	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
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Abstract	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.
AbstractList	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.sup.rCDDP.sup.2500, adapted to 2500 ng/ml CDDP; UKF-PEC-1.sup.r5-FU.sup.500, adapted to 500 ng/ml 5- FU; UKF-PEC1.sup.rCDDP.sup.2500/.sup.r5-FU.sup.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.sup.rCDDP.sup.2500, UKF-PEC-1.sup.r5-FU.sup.500, UKF-PEC1.sup.rCDDP.sup.2500/.sup.r5-FU.sup.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.sup.rCDDP.sup.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.sup.rCDDP.sup.2500 did not display sensitivity to PARP inhibitors. Keywords: Penile carcinomas, Cell lines, Chemoresistance, Homologous recombination deficiency 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. 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.sup.rCDDP.sup.2500, adapted to 2500 ng/ml CDDP; UKF-PEC-1.sup.r5-FU.sup.500, adapted to 500 ng/ml 5- FU; UKF-PEC1.sup.rCDDP.sup.2500/.sup.r5-FU.sup.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.sup.rCDDP.sup.2500, UKF-PEC-1.sup.r5-FU.sup.500, UKF-PEC1.sup.rCDDP.sup.2500/.sup.r5-FU.sup.500, and UKF-PEC-3 (an alternative penis cancer cell line) were tested for sensitivity to paclitaxel, docetaxel, olaparib, and rucaparib. The chemo-resistant sublines differed in their mutational landscapes. UKF-PEC-1.sup.rCDDP.sup.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.sup.rCDDP.sup.2500 did not display sensitivity to PARP inhibitors. 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.BACKGROUND/INTRODUCTIONPenile 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.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-1rCDDP2500, adapted to 2500 ng/ml CDDP; UKF-PEC-1r5-FU500, adapted to 500 ng/ml 5- FU; UKF-PEC1rCDDP2500/r5-FU500, 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-1rCDDP2500, UKF-PEC-1r5-FU500, UKF-PEC1rCDDP2500/r5-FU500, and UKF-PEC-3 (an alternative penis cancer cell line) were tested for sensitivity to paclitaxel, docetaxel, olaparib, and rucaparib.METHODSWe 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-1rCDDP2500, adapted to 2500 ng/ml CDDP; UKF-PEC-1r5-FU500, adapted to 500 ng/ml 5- FU; UKF-PEC1rCDDP2500/r5-FU500, 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-1rCDDP2500, UKF-PEC-1r5-FU500, UKF-PEC1rCDDP2500/r5-FU500, and UKF-PEC-3 (an alternative penis cancer cell line) were tested for sensitivity to paclitaxel, docetaxel, olaparib, and rucaparib.The chemo-resistant sublines differed in their mutational landscapes. UKF-PEC-1rCDDP2500 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-1rCDDP2500 did not display sensitivity to PARP inhibitors.RESULTS AND CONCLUSIONSThe chemo-resistant sublines differed in their mutational landscapes. UKF-PEC-1rCDDP2500 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-1rCDDP2500 did not display sensitivity to PARP inhibitors. 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. Abstract 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-1rCDDP2500, adapted to 2500 ng/ml CDDP; UKF-PEC-1r5-FU500, adapted to 500 ng/ml 5- FU; UKF-PEC1rCDDP2500/r5-FU500, 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-1rCDDP2500, UKF-PEC-1r5-FU500, UKF-PEC1rCDDP2500/r5-FU500, 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-1rCDDP2500 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-1rCDDP2500 did not display sensitivity to PARP inhibitors. 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. 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 CDDP , adapted to 2500 ng/ml CDDP; UKF-PEC-1 5-FU , adapted to 500 ng/ml 5- FU; UKF-PEC1 CDDP / 5-FU , 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 CDDP , UKF-PEC-1 5-FU , UKF-PEC1 CDDP / 5-FU , and UKF-PEC-3 (an alternative penis cancer cell line) were tested for sensitivity to paclitaxel, docetaxel, olaparib, and rucaparib. The chemo-resistant sublines differed in their mutational landscapes. UKF-PEC-1 CDDP 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 CDDP did not display sensitivity to PARP inhibitors.
ArticleNumber	1352
Audience	Academic
Author	Michaelis, Martin Cinatl, Jindrich Vallo, Stefan Winkelmann, Ria Cinatl, Jaroslav Bankov, Katrin Demes, Melanie Grothe, Sebastian Schmitt, Christina Döring, Claudia Rothweiler, Florian Wild, Peter J.
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BackLink	https://www.ncbi.nlm.nih.gov/pubmed/36564761$$D View this record in MEDLINE/PubMed
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Keywords	Penile carcinomas Homologous recombination deficiency Cell lines Chemoresistance
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Snippet	Background/Introduction Penile cancer is a rare disease in demand for new therapeutic options. Frequently used combination chemotherapy with 5 fluorouracil... Penile cancer is a rare disease in demand for new therapeutic options. Frequently used combination chemotherapy with 5 fluorouracil (5-FU) and cisplatin (CDDP)... Background/Introduction Penile cancer is a rare disease in demand for new therapeutic options. Frequently used combination chemotherapy with 5 fluorouracil... Abstract Background/Introduction Penile cancer is a rare disease in demand for new therapeutic options. Frequently used combination chemotherapy with 5...
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SubjectTerms	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
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Title	Increased HRD score in cisplatin resistant penile cancer cells
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