Patient-derived ovarian cancer xenografts re-growing after a cisplatinum treatment are less responsive to a second drug re-challenge: a new experimental setting to study response to therapy

Ricci, Francesca; Fratelli, Maddalena; Guffanti, Federica; Porcu, Luca; Spriano, Filippo; Dell’Anna, Tiziana; Fruscio, Robert; Damia, Giovanna

doi:10.18632/oncotarget.7465

Cited by 24 publications

(20 citation statements)

References 50 publications

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“… 81 , 82 Moreover, DLL1 has been found to be expressed at high levels in patient-derived ovarian cancer xenografts with low sensitivity to cisplatin. 83 …”

Section: Discussionmentioning

confidence: 99%

Transcriptional profiling of NCI/ADR-RES cells unveils a complex network of signaling pathways and molecular mechanisms of drug resistance

Vert¹,

Castro²,

Ribó³

et al. 2018

OTT

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BackgroundOvarian cancer has the highest mortality rate among all the gynecological cancers. This is mostly due to the resistance of ovarian cancer to current chemotherapy regimens. Therefore, it is of crucial importance to identify the molecular mechanisms associated with chemoresistance.MethodsNCI/ADR-RES is a multidrug-resistant cell line that is a model for the study of drug resistance in ovarian cancer. We carried out a microarray-derived transcriptional profiling analysis of NCI/ADR-RES to identify differentially expressed genes relative to its parental OVCAR-8.ResultsGene-expression profiling has allowed the identification of genes and pathways that may be important for the development of drug resistance in ovarian cancer. The NCI/ADR-RES cell line has differential expression of genes involved in drug extrusion, inactivation, and efficacy, as well as genes involved in the architectural and functional reorganization of the extracellular matrix. These genes are controlled through different signaling pathways, including MAPK–Akt, Wnt, and Notch.ConclusionOur findings highlight the importance of using orthogonal therapies that target completely independent pathways to overcome mechanisms of resistance to both classical chemotherapeutic agents and molecularly targeted drugs.

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“… 81 , 82 Moreover, DLL1 has been found to be expressed at high levels in patient-derived ovarian cancer xenografts with low sensitivity to cisplatin. 83 …”

Section: Discussionmentioning

confidence: 99%

Transcriptional profiling of NCI/ADR-RES cells unveils a complex network of signaling pathways and molecular mechanisms of drug resistance

Vert¹,

Castro²,

Ribó³

et al. 2018

OTT

View full text Add to dashboard Cite

show abstract

“…Human A2780 and SKOV-3 cells (5x10 6 cells/mouse) were injected subcutaneously (sc) in immunodeficient mice. The human ovarian PDX MNHOC218 [20] , [21] , containing three copies of the c-Met gene, was implanted sc as viable tumor fragments (2x2 mm) through trocar needles.…”

Section: Methodsmentioning

confidence: 99%

Activity of Pan-Class I Isoform PI3K/mTOR Inhibitor PF-05212384 in Combination with Crizotinib in Ovarian Cancer Xenografts and PDX

Iezzi

Caiola

Broggini

2016

Translational Oncology

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The Phosphatidyl inositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and c-Met signaling pathways are often deregulated in cancer. The two pathways are interconnected and at least c-Met has been implicated in drug resistance. The aim of the study was to assess in ovarian cancer preclinical models, the efficacy and tolerability of a dual PI3K mTOR inhibitor (PF-05212384 or gedatolisib) and a c-Met inhibitor (crizotinib) either as single agents or in combination. In vitro, both PF-05212384 and crizotinib showed a concentration dependent activity in the two ovarian cancer cell lines. The combination of the two did not result in synergistic activity. A subline resistant to gedatolisib was obtained and showed an increased expression of MDR-1 gene. In vivo results show that crizotinib alone did not display any activity in all the tumors investigated, while PF-05212384 alone had some marginal activity. The combination of the two resulted in all the experiments superior to single agents with a good tolerability. Considering that crizotinib did not show activity in the models used, the results indicate that crizotinib is able to potentiate the activity of PF-05212384. Although the activity of the combination was not striking in these three models of ovarian cancer, due to the good tolerability of the combination, the results would suggest the possibility to combine the two drugs in settings in which gedatolisib or crizotinib alone have already some significant activity.

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“…The epithelial to mesenchymal transition in cells of epithelial origin has been identified as a hallmark of cancer and specifically implicated as promoting dissemination and invasiveness during tumorigenesis [46]. In the context of EOC, markers of EMT have been shown to be associated with increased peritoneal dissemination, resistance to chemotherapy, progression-free survival, and overall survival [47][48][49]. To establish the phenotypic characteristics of the 105C cell line as a potential model of EMT in OCCC, we examined the steady-state levels of five canonical epithelial or mesenchymal markers relative to 9 other OCCC cell lines.…”

Section: Genetic and Molecular Characterizationmentioning

confidence: 99%

Characterization of Mutational Status, Spheroid Formation, and Drug Response of a New Genomically-Stable Human Ovarian Clear Cell Carcinoma Cell Line, 105C

Kolendowski

Valdes

Hirte

et al. 2020

Cells

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Ovarian clear cell carcinoma (OCCC) is a rare subtype of gynecological cancer for which well-characterized and authenticated model systems are scarce. We provide an extensive characterization of ‘105C’, a cell line generated from an adenocarcinoma of the clear cell histotype using targeted next-generation sequencing, cytogenetic microarrays, along with analyses of AKT/mTOR signaling. We report that that the 105C cell line is a bona fide OCCC cell line, carrying PIK3CA, PTEN, and ARID1A gene mutations, consistent with OCCC, yet maintain a stable genome as reflected by low copy number variation. Unlike KOC-7c, TOV-21G, and RMG-V OCCC lines also mutated for the above genes, the 105C cells do not carry mutations in mismatch repair genes. Importantly, we show that 105C cells exhibit greater resistance to mTOR inhibition and carboplatin treatment compared to 9 other OCCC cell lines in 3D spheroid cultures. This resistance may be attributed to 105C cells remaining dormant in suspension culture which surprisingly, contrasts with several other OCCC lines which continue to proliferate in long-term suspension culture. 105C cells survive xenotransplantation but do not proliferate and metastasize. Collectively, we show that the 105C OCCC cell line exhibits unique properties useful for the pre-clinical investigation of OCCC pathobiology.

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Patient-derived ovarian cancer xenografts re-growing after a cisplatinum treatment are less responsive to a second drug re-challenge: a new experimental setting to study response to therapy

Cited by 24 publications

References 50 publications

Transcriptional profiling of NCI/ADR-RES cells unveils a complex network of signaling pathways and molecular mechanisms of drug resistance

Transcriptional profiling of NCI/ADR-RES cells unveils a complex network of signaling pathways and molecular mechanisms of drug resistance

Activity of Pan-Class I Isoform PI3K/mTOR Inhibitor PF-05212384 in Combination with Crizotinib in Ovarian Cancer Xenografts and PDX

Characterization of Mutational Status, Spheroid Formation, and Drug Response of a New Genomically-Stable Human Ovarian Clear Cell Carcinoma Cell Line, 105C

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