Novel Therapeutic Insights in Dedifferentiated Liposarcoma: A Role for FGFR and MDM2 Dual Targeting

Dadone‐Montaudie, Bérengère; Laroche-Clary, Audrey; Mongis, Aline; Chamorey, Emmanuel; Mauro, Ilaria Di; Chaire, Vanessa; Finetti, Pascal; Schiappa, Renaud; Loarer, François Le; Birtwisle-Peyrottes, Isabelle; Michiels, Jean‐François; Bertucci, François; Pédeutour, Florence; Italiano, Antoîne; Bianchini, Laurence

doi:10.3390/cancers12103058

Cited by 12 publications

(8 citation statements)

References 50 publications

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“…This has been reported for FGFR1 and FGFR4 in about 30% of DDLPS. Similarly to what was reported for the activating mutations, overexpression of FGFRs also correlated with a poor prognosis [ 40 ]. Moreover, the gene encoding for the FGFR adaptor protein FRS2 is co-amplified with MDM2 on chromosome 12q13–15 in about 90% of DDLPS ( Figure 1 E).…”

Section: The Roles Of Fgf/fgfr Pathway In Gist and Stssupporting

confidence: 71%

Fibroblast Growth Factor Receptor (FGFR) Signaling in GIST and Soft Tissue Sarcomas

Napolitano

Ostler

Jones

et al. 2021

Cells

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Sarcomas are a heterogeneous group of rare malignancies originating from mesenchymal tissues with limited therapeutic options. Recently, alterations in components of the fibroblast growth factor receptor (FGFR) signaling pathway have been identified in a range of different sarcoma subtypes, most notably gastrointestinal stromal tumors, rhabdomyosarcomas, and liposarcomas. These alterations include genetic events such as translocations, mutations, and amplifications as well as transcriptional overexpression. Targeting FGFR has therefore been proposed as a novel potential therapeutic approach, also in light of the clinical activity shown by multi-target tyrosine kinase inhibitors in specific subtypes of sarcomas. Despite promising preclinical evidence, thus far, clinical trials have enrolled very few sarcoma patients and the efficacy of selective FGFR inhibitors appears relatively low. Here, we review the known alterations of the FGFR pathway in sarcoma patients as well as the preclinical and clinical evidence for the use of FGFR inhibitors in these diseases. Finally, we discuss the possible reasons behind the current clinical data and highlight the need for biomarker stratification to select patients more likely to benefit from FGFR targeted therapies.

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Section: The Roles Of Fgf/fgfr Pathway In Gist and Stssupporting

confidence: 71%

Fibroblast Growth Factor Receptor (FGFR) Signaling in GIST and Soft Tissue Sarcomas

Napolitano

Ostler

Jones

et al. 2021

Cells

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“…Similarly, the concomitant use of inhibitors to abolish drug resistance has been shown to be more effective in clinical trials [ 194 , 260 ]. Another promising strategy is combination therapy with TKIs and signaling pathway inhibitors [ 194 , 237 , 261 , 262 ], as well as simultaneous inhibition of FGFRs and induction of apoptosis [ 263 , 264 , 265 ]. Ligand traps and mAbs targeting FGFR/FGF are relatively new approaches and are still relatively few in clinical trials.…”

Section: Discussionmentioning

confidence: 99%

FGF/FGFR-Dependent Molecular Mechanisms Underlying Anti-Cancer Drug Resistance

Szymczyk

Sluzalska

Materla

et al. 2021

Cancers

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Increased expression of both FGF proteins and their receptors observed in many cancers is often associated with the development of chemoresistance, limiting the effectiveness of currently used anti-cancer therapies. Malfunctioning of the FGF/FGFR axis in cancer cells generates a number of molecular mechanisms that may affect the sensitivity of tumors to the applied drugs. Of key importance is the deregulation of cell signaling, which can lead to increased cell proliferation, survival, and motility, and ultimately to malignancy. Signaling pathways activated by FGFRs inhibit apoptosis, reducing the cytotoxic effect of some anti-cancer drugs. FGFRs-dependent signaling may also initiate angiogenesis and EMT, which facilitates metastasis and also correlates with drug resistance. Therefore, treatment strategies based on FGF/FGFR inhibition (using receptor inhibitors, ligand traps, monoclonal antibodies, or microRNAs) appear to be extremely promising. However, this approach may lead to further development of resistance through acquisition of specific mutations, metabolism switching, and molecular cross-talks. This review brings together information on the mechanisms underlying the involvement of the FGF/FGFR axis in the generation of drug resistance in cancer and highlights the need for further research to overcome this serious problem with novel therapeutic strategies.

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“…The amplification of FRS2 is also frequently observed in DDLPS. FRS2 is related to the FGF receptor signaling pathway, suggesting that it may be a therapeutic target [39,40]. Except for the amplification of chromosome 12q13-15, the NCC-DDLPS4-C1 cell line exhibited a loss of 11q23, which was not observed in NCC-DDLPS1-C1 [30], NCC-DDLPS2-C1 [31], and NCC-DDLPS3-C1 [32].…”

Section: Discussionmentioning

confidence: 96%

Establishment and Characterization of NCC-DDLPS4-C1: A Novel Patient-Derived Cell Line of Dedifferentiated Liposarcoma

Tsuchiya

Yoshimatsu²,

Noguchi³

et al. 2021

JPM

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Dedifferentiated liposarcoma (DDLPS) is a highly malignant sarcoma characterized by the co-amplification of MDM2 and CDK4. Although systemic chemotherapy is recommended for unresectable or metastatic cases, DDLPS is insensitive to conventional chemotherapy, leading to an unfavorable prognosis. Therefore, novel treatment methods are urgently required. Patient-derived cell lines are essential in preclinical studies. Recently, large-scale screening studies using a number of cell lines have been actively conducted for the development of new therapeutic drugs. However, the DDLPS cell line cannot be obtained from public cell banks owing to its rarity, hindering screening studies. As such, novel DDLPS cell lines need to be established. Accordingly, this study aimed to establish a novel DDLPS cell line from surgical specimens. The cell line was named NCC-DDLPS4-C1. NCC-DDLPS4-C1 cells retained copy number alterations corresponding to the original tumors. Further, the cells demonstrated constant growth, spheroid formation, and equivalent invasiveness to MG63 osteosarcoma cells. We also conducted drug screening and integrated the results with those of the previously reported DDLPS cell lines. Consequently, we identified the histone deacetylase inhibitor romidepsin as a novel candidate drug. In conclusion, the NCC-DDLPS4-C1 cell line is a useful tool for the basic study of DDLPS.

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Novel Therapeutic Insights in Dedifferentiated Liposarcoma: A Role for FGFR and MDM2 Dual Targeting

Cited by 12 publications

References 50 publications

Fibroblast Growth Factor Receptor (FGFR) Signaling in GIST and Soft Tissue Sarcomas

Fibroblast Growth Factor Receptor (FGFR) Signaling in GIST and Soft Tissue Sarcomas

FGF/FGFR-Dependent Molecular Mechanisms Underlying Anti-Cancer Drug Resistance

Establishment and Characterization of NCC-DDLPS4-C1: A Novel Patient-Derived Cell Line of Dedifferentiated Liposarcoma

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