RESUMEN
Camidanlumab tesirine (ADCT-301) is a CD25-specific antibody-drug conjugate (ADC) employing SG3199, a highly cytotoxic DNA minor groove cross-linking pyrrolobenzodiazepine dimer. The ADC has shown early clinical antitumour activity in various cancers, including B- and T-cell lymphomas. We assessed its preclinical activity as a single agent in 57 lymphoma cell lines and in combination with selected drugs in T-cell lymphoma-derived cell lines. Cells were exposed to increasing concentrations of the ADC or SG3199 for 96 h, followed by an MTT proliferation assay. CD25 expression was measured at cell surface and RNA levels. Experiments with PDX-derived cell lines were used for validation studies. Camidanlumab tesirine presented more potent single agent in vitro cytotoxic activity in T- than B-cell lymphomas. In vitro activity was correlated with CD25 cell surface and RNA expression. In vitro activity was correlated with CD25 cell surface and RNA expression. When camidanlumab tesirine-containing combinations were evaluated in four T-cell lymphoma models, the most active partners were everolimus, copanlisib, venetoclax, vorinostat, and pralatrexate, followed by bortezomib, romidepsin, bendamustine, and 5-azacytidine. The strong camidanlumab tesirine single-agent anti-lymphoma activity and the in vitro synergisms with targeted agents identify potential combination partners for future clinical studies.
RESUMEN
The DNA damage response (DDR) is the cellular process of preserving an intact genome and is often deregulated in lymphoma cells. The ataxia telangiectasia and Rad3-related (ATR) kinase is a crucial factor of DDR in the response to DNA single-strand breaks. ATR inhibitors are agents that have shown considerable clinical potential in this context. We characterized the activity of the ATR inhibitor elimusertib (BAY 1895344) in a large panel of lymphoma cell lines. Furthermore, we evaluated its activity combined with the clinically approved PI3K inhibitor copanlisib in vitro and in vivo. Elimusertib exhibits potent anti-tumour activity across various lymphoma subtypes, which is associated with the expression of genes related to replication stress, cell cycle regulation and, as also sustained by CRISPR Cas9 experiments, CDKN2A loss. In several tumour models, elimusertib demonstrated widespread anti-tumour activity stronger than ceralasertib, another ATR inhibitor. This activity is present in both DDR-proficient and DDR-deficient lymphoma models. Furthermore, a combination of ATR and PI3K inhibition by treatment with elimusertib and copanlisib has in vitro and in vivo anti-tumour activity, providing a potential new treatment option for lymphoma patients.
Asunto(s)
Linfoma , Neoplasias , Humanos , Fosfatidilinositol 3-Quinasas/genética , Proteínas de la Ataxia Telangiectasia Mutada/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias/tratamiento farmacológico , Linfoma/tratamiento farmacológico , Daño del ADNRESUMEN
Antibody-drug conjugates (ADCs) represent one of the most successful therapeutic approaches introduced in clinical practice in the last few years. Loncastuximab tesirine (ADCT-402) is a CD19 targeting ADC, in which the antibody is conjugated through a protease cleavable dipeptide linker to a pyrrolobenzodiazepine (PBD) dimer warhead (SG3199). Based on the results of a phase 2 study, loncastuximab tesirine was recently approved for adult patients with relapsed/refractory large B-cell lymphoma. We assessed the activity of loncastuximab tesirine using in vitro and in vivo models of lymphomas, correlated its activity with CD19 expression levels, and identified combination partners providing synergy with loncastuximab tesirine. Loncastuximab tesirine was tested across 60 lymphoma cell lines. Loncastuximab tesirine had strong cytotoxic activity in B-cell lymphoma cell lines. The in vitro activity was correlated with CD19 expression level and intrinsic sensitivity of cell lines to the ADC's warhead. Loncastuximab tesirine was more potent than other anti-CD19 ADCs (coltuximab ravtansine, huB4-DGN462), albeit the pattern of activity across cell lines was correlated. Loncastuximab tesirine activity was also largely correlated with cell line sensitivity to R-CHOP. Combinatorial in vitro and in vivo experiments identified the benefit of adding loncastuximab tesirine to other agents, especially BCL2 and PI3K inhibitors. Our data support the further development of loncastuximab tesirine as a single agent and in combination for patients affected by mature B-cell neoplasms. The results also highlight the importance of CD19 expression and the existence of lymphoma populations characterized by resistance to multiple therapies.
RESUMEN
Hematological cancers are among the most common cancers in adults and children. Despite significant improvements in therapies, many patients still succumb to the disease. Therefore, novel therapies are needed. The Wiskott-Aldrich syndrome protein (WASp) family regulates actin assembly in conjunction with the Arp2/3 complex, a ubiquitous nucleation factor. WASp is expressed exclusively in hematopoietic cells and exists in two allosteric conformations: autoinhibited or activated. Here, we describe the development of EG-011, a first-in-class small molecule activator of the WASp auto-inhibited form. EG-011 possesses in vitro and in vivo anti-tumor activity as a single agent in lymphoma, leukemia, and multiple myeloma, including models of secondary resistance to PI3K, BTK, and proteasome inhibitors. The in vitro activity was confirmed in a lymphoma xenograft. Actin polymerization and WASp binding was demonstrated using multiple techniques. Transcriptome analysis highlighted homology with drugs-inducing actin polymerization.
RESUMEN
Polatuzumab vedotin is antibody-drug conjugate (ADC) targeting CD79B approved for the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma when given in combination with bendamustine and rituximab. The report by Kawasaki et al. provide hints on what might be happening in lymphoma cells exposed to polatuzumab vedotin and to rituximab and on potential mechanism of resistance to the ADC. Commentary on: Kawasaki et al. The molecular rationale for the combination of polatuzumab vedotin plus rituximab in diffuse large B-cell lymphoma. Br J Haematol 2022;199:245-255.
Asunto(s)
Inmunoconjugados , Linfoma de Células B Grandes Difuso , Antígenos CD20 , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Clorhidrato de Bendamustina/uso terapéutico , Antígenos CD79 , Humanos , Inmunoconjugados/uso terapéutico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/etiología , Rituximab/uso terapéuticoRESUMEN
PI3Kδ inhibitors are active in patients with lymphoid neoplasms and a first series of them have been approved for the treatment of multiple types of B-cell lymphoid tumors, including marginal zone lymphoma (MZL). The identification of the mechanisms underlying either primary or secondary resistance is fundamental to optimize the use of novel drugs. Here we present a model of secondary resistance to PI3Kδ inhibitors obtained by prolonged exposure of a splenic MZL cell line to idelalisib. The VL51 cell line was kept under continuous exposure to idelalisib. The study included detailed characterization of the model, pharmacological screens, silencing experiments, and validation experiments on multiple cell lines and on clinical specimens. VL51 developed resistance to idelalisib, copanlisib, duvelisib, and umbralisib. An integrative analysis of transcriptome and methylation data highlighted an enrichment of upregulated transcripts and low-methylated promoters in resistant cells, including IL-6/STAT3- and PDGFRA-related genes and surface CD19 expression, alongside the repression of the let-7 family of miRNA, and miR-125, miR-130, miR-193 and miR-20. The IL-6R blocking antibody tocilizumab, the STAT3 inhibitor stattic, the LIN28 inhibitor LIN1632, the PDGFR inhibitor masitinib and the anti-CD19 antibody drug conjugate loncastuximab tesirine were active compounds in the resistant cells as single agents and/or in combination with PI3Kδ inhibition. Findings were validated on additional in vitro lymphoma models and on clinical specimens. A novel model of resistance obtained from splenic MZL allowed the identification of therapeutic approaches able to improve the antitumor activity of PI3Kδ inhibitors in B-cell lymphoid tumors.
Asunto(s)
Leucemia Linfocítica Crónica de Células B , Linfoma de Células B de la Zona Marginal , MicroARNs , Humanos , Interleucina-6 , Linfoma de Células B de la Zona Marginal/patología , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
Antibody drug conjugates represent an important class of anti-cancer drugs in both solid tumors and hematological cancers. Here, we report preclinical data on the anti-tumor activity of the first-in-class antibody drug conjugate MEN1309/OBT076 targeting CD205. The study included preclinical in vitro activity screening on a large panel of cell lines, both as single agent and in combination and validation experiments on in vivo models. CD205 was first shown frequently expressed in lymphomas, leukemias and multiple myeloma by immunohistochemistry on tissue microarrays. Anti-tumor activity of MEN1309/OBT076 as single agent was then shown across 42 B-cell lymphoma cell lines with a median IC50 of 200 pM and induction of apoptosis in 25/42 (59.5%) of the cases. The activity appeared highly correlated with its target expression. After in vivo validation as the single agent, the antibody drug conjugate synergized with the BCL2 inhibitor venetoclax, and the anti-CD20 monoclonal antibody rituximab. The first-in-class antibody drug targeting CD205, MEN1309/OBT076, demonstrated strong pre-clinical anti-tumor activity in lymphoma, warranting further investigations as a single agent and in combination.
Asunto(s)
Antineoplásicos , Inmunoconjugados , Linfoma , Anticuerpos Monoclonales/farmacología , Antígenos CD20 , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis , Línea Celular Tumoral , Humanos , Inmunoconjugados/farmacología , Inmunoconjugados/uso terapéutico , Linfoma/tratamiento farmacológico , Rituximab/uso terapéuticoRESUMEN
BIRC3 is a recurrently mutated gene in chronic lymphocytic leukemia (CLL) but the functional implications of BIRC3 mutations are largely unexplored. Furthermore, little is known about the prognostic impact of BIRC3 mutations in CLL cohorts homogeneously treated with first-line fludarabine, cyclophosphamide, and rituximab (FCR). By immunoblotting analysis, we showed that the non-canonical nuclear factor-κB pathway is active in BIRC3-mutated cell lines and in primary CLL samples, as documented by the stabilization of MAP3K14 and by the nuclear localization of p52. In addition, BIRC3-mutated primary CLL cells are less sensitive to flu-darabine. In order to confirm in patients that BIRC3 mutations confer resistance to fludarabine-based chemoimmunotherapy, a retrospective multicenter cohort of 287 untreated patients receiving first-line FCR was analyzed by targeted next-generation sequencing of 24 recurrently mutated genes in CLL. By univariate analysis adjusted for multiple comparisons BIRC3 mutations identify a poor prognostic subgroup of patients in whom FCR treatment fails (median progression-free survival: 2.2 years, P<0.001) similar to cases harboring TP53 mutations (median progression-free survival: 2.6 years, P<0.0001). BIRC3 mutations maintained an independent association with an increased risk of progression with a hazard ratio of 2.8 (95% confidence interval 1.4-5.6, P=0.004) in multivariate analysis adjusted for TP53 mutation, 17p deletion and IGHV mutation status. If validated, BIRC3 mutations may be used as a new molecular predictor to select high-risk patients for novel frontline therapeutic approaches.
Asunto(s)
Leucemia Linfocítica Crónica de Células B , Protocolos de Quimioterapia Combinada Antineoplásica , Proteína 3 que Contiene Repeticiones IAP de Baculovirus , Ciclofosfamida/uso terapéutico , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Mutación , Pronóstico , Estudios Retrospectivos , Rituximab/uso terapéuticoRESUMEN
The activation of the PI3K/AKT/mTOR pathway is a main driver of cell growth, proliferation, survival, and chemoresistance of cancer cells, and, for this reason, represents an attractive target for developing targeted anti-cancer drugs. There are plenty of preclinical data sustaining the anti-tumor activity of dual PI3K/mTOR inhibitors as single agents and in combination in lymphomas. Clinical responses, including complete remissions (especially in follicular lymphoma patients), are also observed in the very few clinical studies performed in patients that are affected by relapsed/refractory lymphomas or chronic lymphocytic leukemia. In this review, we summarize the literature on dual PI3K/mTOR inhibitors focusing on the lymphoma setting, presenting both the three compounds still in clinical development and those with a clinical program stopped or put on hold.
Asunto(s)
Antineoplásicos/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Linfoma/tratamiento farmacológico , Inhibidores de las Quinasa Fosfoinosítidos-3/uso terapéutico , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cromonas/uso terapéutico , Humanos , Terapia Molecular Dirigida , Oligopéptidos/uso terapéutico , Fosfatidilinositol 3-Quinasas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Quinoxalinas/uso terapéutico , Transducción de Señal/efectos de los fármacos , Sulfonamidas/uso terapéuticoRESUMEN
The B-cell receptor and the phosphatidylinositol 3-kinase (PI3K) signalling pathways, together with their downstream partners, represent important therapeutic targets for B-cell lymphomas. Here, we evaluated the activity of acalabrutinib (ACP-196) and ACP-319 (AMG-319), second generation inhibitors of Bruton tyrosine kinase (BTK) and PI3Kδ inhibitor, respectively, in lymphoma pre-clinical models. The two compounds showed activity in activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL), mantle cell lymphoma and marginal zone lymphoma. Two in vivo experiments with ABC DLBCL and MCL xenografts confirmed the effect of the single agents. Benefit was achieved by exposing the lymphoma cell lines to both acalabrutinib and ACP-319. Two cell lines presented a discordant response to first and second generation BTK inhibitors, probably due to the inhibition by ibrutinib of kinases other than BTK. In conclusion, our data sustain the on-going current trials with acalabrutinib and ACP-319 as single agents and provide the basis for the investigation of their combination as well.
Asunto(s)
Adenosina/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Benzamidas/uso terapéutico , Linfoma de Células B/tratamiento farmacológico , Pirazinas/uso terapéutico , Quinolinas/uso terapéutico , Adenosina/administración & dosificación , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Animales , Benzamidas/administración & dosificación , Proliferación Celular/efectos de los fármacos , Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Sinergismo Farmacológico , Humanos , Linfoma de Células B/patología , Linfoma de Células B de la Zona Marginal/tratamiento farmacológico , Linfoma de Células B de la Zona Marginal/patología , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/patología , Ratones SCID , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazinas/administración & dosificación , Quinolinas/administración & dosificación , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Antibody-drug conjugates (ADC) are a novel way to deliver potent cytotoxic compounds to cells expressing a specific antigen. Four ADC targeting CD19, including SAR3419 (coltuximab ravtansine), have entered clinical development. Here, we present huB4-DGN462, a novel ADC based on the SAR3419 anti-CD19 antibody linked via sulfo-SPDB to the potent DNA-alkylating agent DGN462. huB4-DGN462 had improved in vitro anti-proliferative and cytotoxic activity compared to SAR3419 across multiple B-cell lymphoma and human acute lymphoblastic leukemia cell lines. In vivo experiments using lymphoma xenografts models confirmed the in vitro data. The response of B-cell lymphoma lines to huB4-DGN462 was not correlated with CD19 expression, the presence of BCL2 or MYC translocations, TP53 inactivation or lymphoma histology. In conclusion, huB4-DGN462 is an attractive candidate for clinical investigation in patients with B-cell malignancies.
Asunto(s)
Anticuerpos Monoclonales Humanizados/farmacología , Antígenos CD19/metabolismo , Antineoplásicos/farmacología , Inmunoconjugados/farmacología , Leucemia/metabolismo , Linfoma/metabolismo , Maitansina/análogos & derivados , Animales , Anticuerpos Monoclonales Humanizados/química , Antineoplásicos/química , Línea Celular Tumoral , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Inmunoconjugados/química , Leucemia/tratamiento farmacológico , Leucemia/patología , Linfoma/tratamiento farmacológico , Linfoma/patología , Maitansina/química , Maitansina/farmacología , Ratones , Resultado del Tratamiento , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Aberrant changes in microRNA expression contribute to lymphomagenesis. Bromodomain and extra-terminal domain inhibitors such as OTX015 (MK-8628, birabresib) have demonstrated preclinical and clinical activity in hematologic tumors. MicroRNA profiling of diffuse large B-cell lymphoma cells treated with OTX015 revealed changes in the expression levels of a limited number of microRNAs, including miR-92a-1-5p, miR-21-3p, miR-155-5p and miR-96-5p. Analysis of publicly available chromatin immunoprecipitation sequencing data of diffuse large B-cell lymphoma cells treated with bromodomain and extra-terminal domain (BET) inhibitors showed that the BET family member BRD4 bound to the upstream regulatory regions of multiple microRNA genes and that this binding decreased following BET inhibition. Alignment of our microRNA profiling data with the BRD4 chromatin immunoprecipitation sequencing data revealed that microRNAs downregulated by OTX015 also exhibited reduced BRD4 binding in their promoter regions following treatment with another bromodomain and extra-terminal domain inhibitor, JQ1, indicating that BRD4 contributes directly to microRNA expression in lymphoma. Treatment with bromodomain and extra-terminal domain inhibitors also decreased the expression of the arginine methyltransferase PRMT5, which plays a crucial role in B-cell transformation and negatively modulates the transcription of miR-96-5p. The data presented here indicate that in addition to previously observed effects on the expression of coding genes, bromodomain and extra-terminal domain inhibitors also modulate the expression of microRNAs involved in lymphomagenesis.
Asunto(s)
Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica/genética , Linfoma de Células B Grandes Difuso/genética , MicroARNs/genética , Proteínas Nucleares/genética , Dominios Proteicos , Factores de Transcripción/genética , Acetanilidas/farmacología , Proteínas de Ciclo Celular , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Linfoma de Células B Grandes Difuso/metabolismo , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Unión Proteica/efectos de los fármacos , Factores de Transcripción/química , Factores de Transcripción/metabolismoRESUMEN
The epigenome is often deregulated in cancer and treatment with inhibitors of bromodomain and extra-terminal proteins, the readers of epigenetic acetylation marks, represents a novel therapeutic approach. Here, we have characterized the anti-tumour activity of the novel bromodomain and extra-terminal (BET) inhibitor BAY 1238097 in preclinical lymphoma models. BAY 1238097 showed anti-proliferative activity in a large panel of lymphoma-derived cell lines, with a median 50% inhibitory concentration between 70 and 208 nmol/l. The compound showed strong anti-tumour efficacy in vivo as a single agent in two diffuse large B cell lymphoma models. Gene expression profiling showed BAY 1238097 targeted the NFKB/TLR/JAK/STAT signalling pathways, MYC and E2F1-regulated genes, cell cycle regulation and chromatin structure. The gene expression profiling signatures also highly overlapped with the signatures obtained with other BET Bromodomain inhibitors and partially overlapped with HDAC-inhibitors, mTOR inhibitors and demethylating agents. Notably, BAY 1238097 presented in vitro synergism with EZH2, mTOR and BTK inhibitors. In conclusion, the BET inhibitor BAY 1238097 presented promising anti-lymphoma preclinical activity in vitro and in vivo, mediated by the interference with biological processes driving the lymphoma cells. Our data also indicate the use of combination schemes targeting EZH2, mTOR and BTK alongside BET bromodomains.
Asunto(s)
Antineoplásicos/uso terapéutico , Benzodiazepinas/uso terapéutico , Linfoma no Hodgkin/tratamiento farmacológico , Adenina/análogos & derivados , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Benzodiazepinas/administración & dosificación , Benzodiazepinas/farmacología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo/efectos de los fármacos , Sinergismo Farmacológico , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Proteína Potenciadora del Homólogo Zeste 2/biosíntesis , Everolimus/farmacología , Femenino , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Linfoma no Hodgkin/genética , Linfoma no Hodgkin/patología , Ratones SCID , Piperidinas , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirazoles/farmacología , Pirimidinas/farmacología , Células Tumorales Cultivadas/efectos de los fármacos , Células Tumorales Cultivadas/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Despite the marked improvements in the treatment of lymphomas, there is still a need for new therapeutic agents. Synthetic retinoids represent a class of compounds with anti-cancer activity. Here, we report the preclinical activity of a new member of this class, the ST1926-derivative ST5589, in lymphomas. ST5589 presented a dose-dependent anti-proliferative activity in almost all of the 25 lymphoma cell lines analysed, with a median 50% inhibitory concentration of 433 nM. Apoptosis was observed in 8/11 cell lines. ST5589 induced changes in the gene expression profiles of the cell lines, including the down-regulation of Aurora Kinase A (AURKA). Specific gene expression signatures were associated with a higher sensitivity to the compound and combination of ST5589 with carfilzomib revealed the importance of proteasome activity in mediating the anti-tumour activity of ST5589. In conclusion, we have identified a new mechanism of action of atypical retinoids as anti-cancer compounds, and the encouraging results obtained with the new ST1926-derivative ST5589 provide the basis for further developments of the compound.
Asunto(s)
Aurora Quinasa A/biosíntesis , Regulación hacia Abajo/efectos de los fármacos , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Linfoma/tratamiento farmacológico , Proteínas de Neoplasias/biosíntesis , Retinoides/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Linfoma/enzimología , Linfoma/patologíaRESUMEN
The role of EGF and TGF-ß1 in thyroid cancer is still not clearly defined. TGF-ß1 inhibited the cellular growth and migration of follicular (FTC-133) and papillary (B-CPAP) thyroid carcinoma cell lines. Co-treatments of TGF-ß1 and EGF inhibited proliferation in both cell lines, but displayed opposite effect on their migratory capability, leading to inhibition in B-CPAP and promotion in FTC-133 cells, by a MAPK-dependent mechanism. TGF-ß1, TßRII and EGFR expressions were evaluated in benign and malignant thyroid tumors. Both positivity (51.7% and 60.0% and 80.0% in FA and PTC and FTC) and overexpression (60.0%, 77.7% and 75.0% in FA, PTC and FTC) of EGFR mRNA correlates with the aggressive tumor behavior. The moderate overexpression of TGF-ß1 and TßRII mRNA in PTC tissues (61.5% and 62.5%, respectively), counteracted their high overexpression in FTC tissues (100% and 100%, respectively), while EGFR overexpression was similar in both carcinomas. Papillary carcinomas were positive to E-cadherin expression, while the follicular carcinomas lose E-cadherin staining. Our findings of TGF-ß1/TßRII and EGFR overexpressions together with a loss of E-cadherin observed in human follicular thyroid carcinomas, and of increased migration ability MAPK-dependent after EGF/TGF-ß1 treatments in the follicular thyroid carcinoma cell line, reinforced the hypothesis of a cross-talk between EGF and TGF-ß1 systems in follicular thyroid carcinomas phenotype.