Publications by authors named "F Pedeutour"

166 Publications

Molecular follow-up of first-line treatment by osimertinib in lung cancer: Importance of using appropriate tools for detecting EGFR resistance mutation C797S.

Cancer Genet 2021 Aug 10;256-257:158-161. Epub 2021 Jun 10.

Laboratory of Solid Tumor Genetics, University Hospital of Nice-Côte d'Azur University, Nice, France; Laboratory of Solid Tumor Genetics, Institute for Research on Cancer and Aging of Nice (IRCAN), CNRS UMR 7284/INSERM U1081, Nice, France. Electronic address:

The C797S mutation encoded by EGFR exon 20 is classically observed as a tertiary event in EGFR-mutant non-small-cell lung carcinoma (NSCLC) primarily treated by first generation tyrosine kinase inhibitors (TKI) and secondarily treated by third-generation TKI, such as osimertinib, if the EGFR-T790M resistance mutation is detected. Recently, significant prolonged progression free survival has been observed following first-line osimertinib, in EGFR-mutant NSLC. While mechanisms of molecular resistance to first-generation TKI have been well studied, little is known about resistance induced by primary third-generation TKI treatments. We report the case of a 65 year-old female treated by first-line osimertinib for a multimetastatic exon 19-EGFR-mutant NSCLC. EGFR-C797S resistance mutation and PIK3CA mutation were detected together with the remaining EGFR-exon 19 deletion. This observation provides insights of acquired resistance to first line-osimertinib. It also highlights the importance of making molecular platforms which perform routine EGFR testing in lung cancer aware of the kind of therapeutic protocols given to the patient. Indeed, for rapid results or low-costs procedures, some targeted methods specifically targeting T790M may be used at relapse and may overlook alterations such as C797S or PIK3CA mutations. Targeted next generation sequencing is therefore a recommended option.
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http://dx.doi.org/10.1016/j.cancergen.2021.06.001DOI Listing
August 2021

Single-cell RNA sequencing reveals intratumoral heterogeneity in primary uveal melanomas and identifies HES6 as a driver of the metastatic disease.

Cell Death Differ 2021 Jun 18;28(6):1990-2000. Epub 2021 Jan 18.

Université Côte d'Azur, Nice, France.

Intratumor heterogeneity has been recognized in numerous cancers as a major source of metastatic dissemination. In uveal melanomas, the existence and identity of specific subpopulations, their biological function and their contribution to metastasis remain unknown. Here, in multiscale analyses using single-cell RNA sequencing of six different primary uveal melanomas, we uncover an intratumoral heterogeneity at the genomic and transcriptomic level. We identify distinct transcriptional cell states and diverse tumor-associated populations in a subset of the samples. We also decipher a gene regulatory network underlying an invasive and poor prognosis state driven in part by the transcription factor HES6. HES6 heterogenous expression has been validated by RNAscope assays within primary human uveal melanomas, which further unveils the existence of these cells conveying a dismal prognosis in tumors diagnosed with a favorable outcome using bulk analyses. Depletion of HES6 impairs proliferation, migration and metastatic dissemination in vitro and in vivo using the chick chorioallantoic membrane assay, demonstrating the essential role of HES6 in uveal melanomas. Thus, single-cell analysis offers an unprecedented view of primary uveal melanoma heterogeneity, identifies bona fide biomarkers for metastatic cells in the primary tumor, and reveals targetable modules driving growth and metastasis formation. Significantly, our findings demonstrate that HES6 is a valid target to stop uveal melanoma progression.
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http://dx.doi.org/10.1038/s41418-020-00730-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185008PMC
June 2021

Superficial CD34-positive Fibroblastic Tumour: Unique Subungual Presentation with Confounding Clinical Findings Resembling Fibrokeratoma-like Bowen's Disease.

Acta Derm Venereol 2021 Feb 11;101(2):adv00388. Epub 2021 Feb 11.

Central Laboratory of Pathology, Nice University Hospital, 30, Avenue Voie Romaine- CS 51069, FR-06001 Nice, Cedex 1, France.

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http://dx.doi.org/10.2340/00015555-3727DOI Listing
February 2021

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

Cancers (Basel) 2020 Oct 20;12(10). Epub 2020 Oct 20.

Institute for Research on Cancer and Aging, Nice (IRCAN), Institut National de la Santé et de la Recherche Médicale (INSERM) U1081, Centre National de la Recherche Scientifique (CNRS) UMR7284, Université Côte d'Azur, 06107 Nice, France.

We aimed to evaluate the therapeutic potential of the pan-FGFR inhibitor erdafitinib to treat dedifferentiated liposarcoma (DDLPS). FGFR expression and their prognostic value were assessed in a series of 694 samples of well-differentiated/dedifferentiated liposarcoma (WDLPS/DDLPS). The effect of erdafitinib-alone or in combination with other antagonists-on tumorigenicity was evaluated in vitro and in vivo. We detected overexpression of FGFR1 and/or FGFR4 in a subset of WDLPS and DDLPS and demonstrated correlation of this expression with poor prognosis. Erdafitinib treatment reduced cell viability, inducing apoptosis and strong inhibition of the ERK1/2 pathway. Combining erdafitinib with the MDM2 antagonist RG7388 exerted a synergistic effect on viability, apoptosis, and clonogenicity in one WDLPS and two DDLPS cell lines. Efficacy of this combination was confirmed in vivo on a DDLPS xenograft. Importantly, we report the efficacy of erdafitinib in one patient with refractory DDLPS showing disease stabilization for 12 weeks. We provide evidence that the FGFR pathway has therapeutic potential for a subset of DDLPS and that an FGFR1/FGFR4 expression might constitute a powerful biomarker to select patients for FGFR inhibitor clinical trials. In addition, we show that combining erdafitinib with RG7388 is a promising strategy for patients with DDLPS that deserves further investigation in the clinical setting.
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http://dx.doi.org/10.3390/cancers12103058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589658PMC
October 2020

A Multicenter Phase II Study of Pazopanib in Patients with Unresectable Dermatofibrosarcoma Protuberans.

J Invest Dermatol 2021 Apr 18;141(4):761-769.e2. Epub 2020 Sep 18.

Team 1, HIPI, INSERM U976, Université de Paris, Paris, France; Department of Dermatology, Hôpital Saint-Louis AP-HP, Paris, France.

Dermatofibrosarcoma protuberans (DFSP) is a soft-tissue sarcoma characterized by a high risk of local infiltration. The identification of the COL1A1-PDGFB t(17;22) translocation activating the PDGF pathway led to the use of imatinib in unresectable DFSP, with a response rate of 36-80%. Pazopanib is a multitarget tyrosine kinase inhibitor approved for soft-tissue sarcomas. We conducted a phase II study of patients with unresectable DFSP to evaluate the efficacy and safety of pazopanib. Patients received 800 mg of pazopanib daily. The primary endpoint was the objective response rate defined as the reduction of the largest diameter of the tumor by ≥30% at 6 months or at surgery. A total of 23 patients, including one pretreated with imatinib, were enrolled. With a median follow-up of 6.2 months (interquartile range = 5.6-7.8 months), five patients (22%, 95% confidence interval = 7-22%) had a partial response to pazopanib. The best objective response rate was 30% (95% confidence interval = 13-53%) using Response Evaluation Criteria in Solid Tumors. One patient with metastatic DFSP previously treated with imatinib died after 2.4 months. Nine patients (39%) discontinued the treatment owing to adverse events. Pharmacodynamics analyses of tumor samples were conducted: the enrichment of EGF and the EGFR-associated gene panel was associated with resistance, suggesting that EGFR-targeted therapies could be a therapeutic option to explore in DFSP. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01059656.
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http://dx.doi.org/10.1016/j.jid.2020.06.039DOI Listing
April 2021
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