Introduction: The incidence of oesophageal cancer (OC) is increasing. Targeted therapies are being investigated, as chemotherapy in advanced OC achieves only 50% response rates and confers significant toxicity. TRANS-COG is a sub-study of COG, the only randomised trial of the Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI) gefitinib versus placebo in patients with advanced OC. Aim and Methods: The aim of TRANS-COG is to identify biomarkers for predicting response to gefitinib by investigating the frequency of mutations of EGFR pathway members and EGFR gene copy number gain (CNG) by Fluorescence In Situ Hybridisation (FISH). Results: No EGFR mutations were identified, frequency of other pathway member mutations are as follows: KRAS 3.6%, PI3KCA 3.2%, BRAF 0.6%. The frequency of EGFR CNG was 13.5%. There were two cases of combined EGFR CNG and KRAS mutation 0.3%.Patients with EGFR CNG tumours had improved OS with gefitinib compared to placebo, log rank p=0.033, HR 0.523 (95%CI 0.285-0.962). Those with EGFR high CNG (amplification) also had improved OS with gefitinib, median OS 4.40 months vs median OS 1.71 months for placebo log rank p=0.004, HR 0.184 (95% CI 0.052-0.653). Mutation of KRAS conferred poor prognosis, independent of treatment received; median OS 3.614 months in KRAS wild type vs 1.741 months in KRAS mutated tumours, log rank p=0.023, HR 1.8153 (95% CI 1.078 3.187). A novel KRAS codon 61 mutation, Q61L, was also identified. Conclusion: 21.18% of patients have dysregulation of the EGFR pathway, these abnormalities represent realistic therapeutic targets. This analysis demonstrates clinical utility of EGFR CNG as a predictive biomarker of gefitinib response.

The Tec family tyrosine kinases Itk, Tec and Rlk are expressed in T cells. Previous studies have established that these kinases are critical for TCR signaling, leading to the activation of PLCγ1. To further understand the functions of Tec kinases in T cell activation, we took three different approaches. First, we performed a thorough analysis of CD28-mediated signaling events and functional responses with purified naïve T cells from Itk-/- mice and a highly controlled stimulation system. Data from this set of studies definitively demonstrate that CD28 costimulation functions efficiently in naïve CD4+ T cells in the absence of Itk. Second, in order to further study the functions of Tec kinases in vivo, we generated transgenic mouse lines expressing a kinase-dead (KD) mutant of Tec on the Itk-/-Rlk-/- background, hoping to study mice that are functionally deficient for all three Tec kinases. The results hint the importance of the Tec kinases in T cell development and/or survival. Finally, in order to identify potential transcriptional targets of Itk, we used microarray technology to compare global gene expression profiles of naïve and stimulated Itk-/- versus Itk+/- CD4+ T cells. This analysis provided a short list of differentially expressed genes in Itk-/- versus Itk+/- CD4 T cells, providing a starting point for further studies of Itk in T cell activation. Collectively, these studies clarified the role of Itk in CD28 signaling, revealed some unexpected aspects of Tec family kinases in T cells, and indicated potential targets of Itk-dependent signaling pathways in T cells.

Medullary thyroid carcinoma (MTC) is a rare malignant tumor originating from thyroid parafollicular C cells. This tumor accounts for 3-4% of thyroid gland neoplasias. MTC may occur sporadically or inherited. The hereditary MTC is part of syndromes of multiple endocrine neoplasia (MEN) 2A and 2B, familial medullary thyroid carcinoma (FMTC). Germline mutations of the RET (REarranged during Transfection) protooncogene cause hereditary form of cancer, whereas somatic mutations can be present in sporadic form of the disease. The RET gene encodes a receptor tyrosine kinase involved in the activation of intracellular signaling pathways leading to proliferation, growth, differentiation, migration and survival. Nowadays, the only possibility of cure for MTC patients consists of total thyroidectomy associated with lymph node dissection. Based on the knowledge of the pathogenic mechanisms of MTC, new drugs have been developed in attempt to control metastatic disease. Of these, the small-molecule tyrosine kinase inhibitors (TKIs) represent one of the most promising agents for MTC treatment and clinical trials have shown encouraging results. Hopefully, the cumulative knowledge about the targets of action of these drugs as well as TKI-associated side effects will help on choosing the best therapeutic approach in order to enhance its benefits.

Introdução: Os inibidores tirosino-quinase (ITQs) constituem uma nova terapia molecular para o carcinoma medular da tireoide (CMT). O vandetanibe, um ITQ que atua contra os receptores VEGFR, EGFR e RET, inibe a transformação e o crescimento do tumor no CMT. No entanto, os ITQs têm importantes efeitos adversos, incluindo o hipotireoidismo. O aumento da expressão da iodotironina desiodase do tipo 3 (D3/DIO3), uma enzima chave na inativação dos hormônios da tireoide, pode ser um possível mecanismo de indução do hipotireoidismo por estas drogas. Objetivo: Investigar os efeitos dos inibidores tirosino-quinase na expressão da D3 em células derivadas do CMT. Métodos: Estudo experimental in vitro, utilizando linhagem de células humanas oriundas de CMT (células TT). As células foram cultivadas em meio específico e tratadas com diferentes doses do ITQ vandetanibe (0,25; 0,5 e 1μM) ou com DMSO. A proliferação celular foi determinada por contagem em câmara de Neubauer. A expressão do mRNA foi avaliada por meio de PCR em tempo real, a expressão proteica por meio de Western Blot e a atividade da D3 foi avaliada por meio da técnica de cromatografia em colunas de Sephadex LH-20. Resultados: A adição do vandetanibe ao meio de cultura causou diminuição do número de células e seu efeito foi tempo e dose dependente, apresentando uma redução máxima (77%) após 6 dias de tratamento na dose de 1μM. Como esperado, o tratamento com vandetanibe inibiu a fosforilação do ERK. Não foram observadas alterações significativas dos níveis de mRNA da DIO3 após 3 (0,02 vs. 0,02 vs. 0,01 vs. 0,01; P = 0,34) ou 6 dias (0,02 vs. 0,02 vs. 0,03 vs. 0,02; P = 0,33) de tratamento. Consequentemente, a expressão proteica da D3 não aumentou nos grupos tratados. No entanto, observou-se um aumento de 2 a 5 vezes na atividade da D3 após 3 dias de tratamento e um aumento de 1,5 a 2,15 vezes em 6 dias de tratamento. Conclusões: O tratamento com vandetanibe não foi associado com níveis aumentados de expressão do mRNA e da proteína da D3 em células derivadas de CMT, embora tenha sido observado um aumento na sua atividade enzimática. / Background: Tyrosine kinase inhibitors (TKIs) constitute a novel molecular therapy for medullary thyroid carcinoma (MTC). Vandetanib, a TKI that acts against the VEGFR, EGFR and RET receptors, inhibits tumor transformation and growth in MTC. However, TKIs have important adverse effects, including hypothyroidism. Increases in the expression of type 3 iodothyronine deiodinase (D3/DIO3), a key enzyme in the inactivation of thyroid hormones, may be a possible mechanism of induction of hypothyroidism by these drugs. Objective: To investigate the effects of vandetanib on D3 expression in MTC-derived cells. Methods: In vitro experimental study using human MTC cell line (TT cells). Cells were cultured in specific medium and treated with different doses of vandetanib (0.25, 0.5 and 1μM) or DMSO. Cell proliferation was determined by counting in Neubauer's chamber. Expression of mRNA was evaluated by real-time PCR, protein expression by Western Blot and D3 activity was evaluated by Sephadex LH-20 column chromatography. Results: The addition of vandetanib to the culture medium caused a time and dose-dependent decrease in the number of cells, with a maximum reduction (77%) after 6 days of treatment at 1μM dose. As expected, vandetanib treatment inhibited ERK phosphorylation. No significant changes in DIO3 mRNA levels were observed after 3 (0.02 vs. 0.02 vs. 0.01 vs. 0.01; P = 0.34) or 6 days (0.02 vs. 0.02 vs. 0.03 vs. 0.02; P = 0.33) of treatment. Accordingly, D3 protein expression did not increase in treated groups. However, we observed a 2 to 5-fold increase in D3 activity after 3 days of treatment and a 1.5 to 2.15-fold increase in 6 days of treatment. Conclusions: Treatment with vandetanib was not associated with increased DIO3 mRNA and D3 protein expression levels in MTC-derived cells, although an increase in enzyme activity has been observed.

Made available in DSpace on 2016-08-29T15:34:30Z (GMT). No. of bitstreams: 1 tese_6281_Dissertação_Roberta Bitencourt Moreira_2013.pdf: 2949871 bytes, checksum: 0c46a98a4735b38e93978376b508fac6 (MD5) Previous issue date: 2013-03-06 / A Leucemia mielóide crônica (LMC) é caracterizada por uma alteração citogenética conhecida, o cromossomo Philadelphia (Ph),resultado da translocação recíproca t(9;22)(q34;q11).O gene de fusão bcr-abl codifica uma proteína de fusão com atividade tirosina cinase aumentada que desregula vias de transdução de sinais ligadas a proliferação, apoptose e diferenciação celular. A evolução natural da LMC quando não tratada é trifásica, mas atualmente, esta dinâmica foi alterada a partir do desenvolvimento dos inibidores de tirosina cinase (ITC). O imatinibe (Glivec®, Novartis) foi o primeiro ITC aprovado para o tratamento da LMC. A atualização de oito anos do estudo internacional randomizado do interferon e imatinibe (IRIS), ratificou a eficácia e a segurança do uso de imatinibea longo prazo com uma sobrevida global de 85% e uma sobrevida livre de evento de 81%.Entretanto, algumas mutações no domínio cinasedo gene bcr-ablconferem resistência elevada a um ou mais ITC influenciando a escolha da terapia subsequente como no caso de uma mutação T315I, que é altamente resistente ao imatinibe.Apesar de múltiplos fatores contribuírem para a resistência ao imatinibe, a presença de mutação é mais prevalente e tem sido a mais investigada. Diante disso, foram selecionados pacientes de dois hospitais da Região da Grande Vitória que realizam atendimento aos pacientes portadores de LMC pelo Sistema Único de Saúde (SUS) que são encaminhados para o Laboratório de Biologia Molecular do Centro de Transplante de Medula Óssea (CEMO) do Instituto Nacional de Câncer (INCA) para avaliação da resposta molecular aos ITCs, para análise de mutação. Também foi desenvolvido um banco de dados no Microsoft Access® para LMCque permite relacionar informações clínicas e laboratoriais de citogenética e biologia molecular, facilitando o acompanhamento de pacientes com LMC, a compreensão da evolução da doença e o desenvolvimento de pesquisas biotecnológicas. / The chronic myeloid leukemia (CML) is characterized by a cytogenetic alteration known as Philadelphia chromosome (Ph), a result of reciprocal translocation t (9; 22) (q34; q11). The resulting fusion bcr-abl gene encodes a protein with tyrosine kinase constitutive activity that deregulates signal transduction inducing proliferation, apoptosis, and cellular differentiation. The natural evolution of CML is currently changing with the development of tyrosine kinase inhibitors (TKI). Imatinib (Gleevec® , Novartis) was the first TKI approved for the treatment of CML. The eight-year update of the international randomized study of interferon and imatinib (IRIS), confirmed the efficacy and safety of imatinib in the long term with an overall survival of 85% and an event-free survival of 81%. However, some mutations in the kinase domain BCR-ABL confer resistance to one or more TKI, influencing the choice of therapy, as in the case of a T315I mutation, which is highly resistant to imatinib. Although many factors contribute to the resistance to imatinib, the presence of mutations is more prevalent and has been further investigated. Therefore, were aimed to perform mutation analysis in patients with a resistant phenotype of two cancer reference hospitals in Vitoria, ES, Brazil. We also developed a CML database relating clinical information and laboratory cytogenetics and molecular biology results, facilitating the monitoring of CML patients, as well as the understanding of disease progression.

Introdução: Os inibidores tirosino-quinase (ITQs) constituem uma nova terapia molecular para o carcinoma medular da tireoide (CMT). O vandetanibe, um ITQ que atua contra os receptores VEGFR, EGFR e RET, inibe a transformação e o crescimento do tumor no CMT. No entanto, os ITQs têm importantes efeitos adversos, incluindo o hipotireoidismo. O aumento da expressão da iodotironina desiodase do tipo 3 (D3/DIO3), uma enzima chave na inativação dos hormônios da tireoide, pode ser um possível mecanismo de indução do hipotireoidismo por estas drogas. Objetivo: Investigar os efeitos dos inibidores tirosino-quinase na expressão da D3 em células derivadas do CMT. Métodos: Estudo experimental in vitro, utilizando linhagem de células humanas oriundas de CMT (células TT). As células foram cultivadas em meio específico e tratadas com diferentes doses do ITQ vandetanibe (0,25; 0,5 e 1μM) ou com DMSO. A proliferação celular foi determinada por contagem em câmara de Neubauer. A expressão do mRNA foi avaliada por meio de PCR em tempo real, a expressão proteica por meio de Western Blot e a atividade da D3 foi avaliada por meio da técnica de cromatografia em colunas de Sephadex LH-20. Resultados: A adição do vandetanibe ao meio de cultura causou diminuição do número de células e seu efeito foi tempo e dose dependente, apresentando uma redução máxima (77%) após 6 dias de tratamento na dose de 1μM. Como esperado, o tratamento com vandetanibe inibiu a fosforilação do ERK. Não foram observadas alterações significativas dos níveis de mRNA da DIO3 após 3 (0,02 vs. 0,02 vs. 0,01 vs. 0,01; P = 0,34) ou 6 dias (0,02 vs. 0,02 vs. 0,03 vs. 0,02; P = 0,33) de tratamento. Consequentemente, a expressão proteica da D3 não aumentou nos grupos tratados. No entanto, observou-se um aumento de 2 a 5 vezes na atividade da D3 após 3 dias de tratamento e um aumento de 1,5 a 2,15 vezes em 6 dias de tratamento. Conclusões: O tratamento com vandetanibe não foi associado com níveis aumentados de expressão do mRNA e da proteína da D3 em células derivadas de CMT, embora tenha sido observado um aumento na sua atividade enzimática. / Background: Tyrosine kinase inhibitors (TKIs) constitute a novel molecular therapy for medullary thyroid carcinoma (MTC). Vandetanib, a TKI that acts against the VEGFR, EGFR and RET receptors, inhibits tumor transformation and growth in MTC. However, TKIs have important adverse effects, including hypothyroidism. Increases in the expression of type 3 iodothyronine deiodinase (D3/DIO3), a key enzyme in the inactivation of thyroid hormones, may be a possible mechanism of induction of hypothyroidism by these drugs. Objective: To investigate the effects of vandetanib on D3 expression in MTC-derived cells. Methods: In vitro experimental study using human MTC cell line (TT cells). Cells were cultured in specific medium and treated with different doses of vandetanib (0.25, 0.5 and 1μM) or DMSO. Cell proliferation was determined by counting in Neubauer's chamber. Expression of mRNA was evaluated by real-time PCR, protein expression by Western Blot and D3 activity was evaluated by Sephadex LH-20 column chromatography. Results: The addition of vandetanib to the culture medium caused a time and dose-dependent decrease in the number of cells, with a maximum reduction (77%) after 6 days of treatment at 1μM dose. As expected, vandetanib treatment inhibited ERK phosphorylation. No significant changes in DIO3 mRNA levels were observed after 3 (0.02 vs. 0.02 vs. 0.01 vs. 0.01; P = 0.34) or 6 days (0.02 vs. 0.02 vs. 0.03 vs. 0.02; P = 0.33) of treatment. Accordingly, D3 protein expression did not increase in treated groups. However, we observed a 2 to 5-fold increase in D3 activity after 3 days of treatment and a 1.5 to 2.15-fold increase in 6 days of treatment. Conclusions: Treatment with vandetanib was not associated with increased DIO3 mRNA and D3 protein expression levels in MTC-derived cells, although an increase in enzyme activity has been observed.

Medullary thyroid carcinoma (MTC) is a rare malignant tumor originating from thyroid parafollicular C cells. This tumor accounts for 3-4% of thyroid gland neoplasias. MTC may occur sporadically or inherited. The hereditary MTC is part of syndromes of multiple endocrine neoplasia (MEN) 2A and 2B, familial medullary thyroid carcinoma (FMTC). Germline mutations of the RET (REarranged during Transfection) protooncogene cause hereditary form of cancer, whereas somatic mutations can be present in sporadic form of the disease. The RET gene encodes a receptor tyrosine kinase involved in the activation of intracellular signaling pathways leading to proliferation, growth, differentiation, migration and survival. Nowadays, the only possibility of cure for MTC patients consists of total thyroidectomy associated with lymph node dissection. Based on the knowledge of the pathogenic mechanisms of MTC, new drugs have been developed in attempt to control metastatic disease. Of these, the small-molecule tyrosine kinase inhibitors (TKIs) represent one of the most promising agents for MTC treatment and clinical trials have shown encouraging results. Hopefully, the cumulative knowledge about the targets of action of these drugs as well as TKI-associated side effects will help on choosing the best therapeutic approach in order to enhance its benefits.

Tie1 é um receptor tirosina quinase expresso em células endoteliais importante em angiogênese, formação de vasos sanguíneos a partir de vasos pré-existentes. Este receptor pertence a uma família pequena composta por apenas dois membros (Tie1 e Tie2) para os quais angiopoietinas foram identificadas como ligantes de Tie2. No entanto, Tie1 continua a ser um receptor órfão, sem ligantes identificados até o momento. Sendo assim, é difícil compreender completamente as propriedades biológicas de Tie1 e seus mecanismos moleculares em angiogênese sem um ligante identificado. Entretanto, como sugerido através de estudos de deleção gênica, este receptor é uma molécula essencial na angiogênese, apresentando um papel importante no desenvolvimento da vascularização da retina e desenvolvimento de tumores. O nosso objetivo foi estudar a participação do domínio extracelular de Tie1 na neovascularização e, no processo, identificar possíveis ligantes para este receptor. Através da tecnologia de phage display, identificamos um peptídeo específico e seletivo para Tie1, sugerindo a existência de um sítio de ligação único neste receptor. Mostramos que este peptídeo é capaz de inibir a proliferação de células endoteliais induzida por Ang1, um ligante bem caracterizado de Tie2 que também modula a atividade de Tie1. Além disso, também mostramos que este peptídeo inibe a angiogênese in vivo num modelo animal bastante relevante para estudo de doenças humanas, o modelo da retinopatia induzida por oxigênio. Uma vez que este peptídeo liga-se a um sítio único e seletivo para Tie1, hipotetizamos que o mesmo poderia mimetizar possíveis ligantes naturais deste receptor. Para identificá-los, proteínas com mimetopo cruzado com este peptídeo foram identificadas em extrato proteico de diferentes linhagens celulares. Tais proteínas são possíveis candidatos a interação com Tie1. Em resumo, demonstramos que o domínio extracelular de Tie1 é importante para a angiogênese patológica e identificamos proteínas como possíveis ligantes deste receptor, o que poderá contribuir para um melhor entendimento da participação de Tie1 na formação de vasos. O peptídeo aqui identificado poderá ser ainda uma ferramenta útil para o desenvolvimento de novas terapias anti-angiogênicas com importantes aplicações à saúde humana. / Tie1 is a tyrosine kinase receptor expressed by endothelial cells and important in angiogenesis, the formation of new blood vessels from pre-existing ones. This receptor belongs to a small family of receptors composed of two members only (Tie1 and Tie2) to which angiopoietins have been identified as ligands for Tie2. On the other hand, Tie1 is still an orphan receptor with no ligand identified to date. Thus, it is difficult to assess Tie1 mechanism of action in neovascularization without a known ligand. Nevertheless, gene deletion studies have shown that Tie1 is essential in angiogenesis, and plays an important role in retinal and tumoral vascularization. The aim of our study was to evaluate the participation of Tie1 extracellular domain in angiogenesis, and in the process, to identify putative ligands for this receptor. Utilizing phage display, we have identified and characterized a Tie1 specific and selective ligand peptide, which suggests the existence of a binding site unique to this receptor and not shared by other family members. We show that this peptide prevents endothelial cells proliferation, induced by angiopoetin-1, a ligand for Tie2 but which also modulates Tie1 activity. Using a well-accepted mouse model for human diseases, the oxygen induced retinopathy model, we show that this peptide inhibits angiogenesis in vivo. Since this peptide maps to a unique binding site in Tie1, we hypothesized that it might mimic a natural ligand for this receptor. To identify them, proteins with cross reactive epitopes with an anti-peptide sera were identified by proteomic approaches. These proteins are thus possible ligands for Tie1. In summary, we have shown that Tie1 extracellular domain is important in angiogenesis and we have identified putative ligand for this receptor, which might contribute to a better understanding of the molecular mechanisms associated with Tie1 in blood vessel formation. The peptide here characterized may also be an important tool for the development of novel anti-angiogenesis therapeutic approaches for disesase with an angiogenic component.

Le but des travaux est de caractériser l’influence de la signalisation VEGF, en particulier la signalisation autocrine VEGF, sur la biologie et la sensibilité/résistance aux médicaments anticancéreux de cellules de cancer colorectal. Nous avons souhaité caractériser l’impact de la signalisation autocrine VEGF dans des modèles de CRC avec une résistance naturelle au bevacizumab, un anticorps anti-VEGF. Bien que ce composé soit actif dans le CRC, une sous population de patients ne répondent pas au traitement. Nos résultats montrent une sur régulation de la voie autocrine HIF-VEGF-VEGFR en réponse à une exposition prolongée au bevacizumab dans les cellules bevacizumab résistantes. Si la résistance à cet anticorps est bien établie, d’autres inhibiteur de la voie VEGF restent actifs (comme la petite molécule ciblée nintedanib) et peuvent inhiber la voie mTOR. La signalisation VEGF autocrine joue un rôle dans la survie de cellules de CRC. Chez les sujets résistants au bevacizumab, il serait intéressant d’introduire le nintedanib seul ou en combinaison pour accentuer l’inhibition angiogénique. Une autre combinaison d’agents (anti VEGF(R) et anti EGFR) a montré une efficacité dans des modèles de CRC en préclinique. La combinaison du bevacizumab et d’une petite molécule ciblant EGFR (erlotinib) a montré une plus grande efficacité que le bevacizumab seul dans des modèles de CRC indépendamment du statut KRAS. Le bevacizumab induit une activation de la voie de survie EGFR dans les cellules tumorales et dans les cellules endothéliales associées à la tumeur. Cette activation se trouve diminuée avec l’introduction de l’erlotinib. Les résultats indiquent que la combinaison du bevacizumab et de l’erlotinib sont plus actif en thérapie de maintenance que le bevacizumab seul, même pour les patients mutés KRAS. Ces résultats ont mené à l’étude clinique positive GERCOR phase III DREAM dans le cancer du côlon métastatique. / The aim of the work is to characterize the influence of VEGF signaling , especially autocrine VEGF signaling , the biology and susceptibility / resistance to anticancer drugs of colorectal cancer cells. We wished to characterize the impact of the autocrine VEGF signaling in CRC models with natural resistance to bevacizumab , an anti -VEGF antibody. Although this compound is active in the CRC, a subpopulation of patients do not respond to treatment. Our results show an autocrine regulatory pathway HIF- VEGF- VEGFR in response to prolonged exposure to bevacizumab in bevacizumab resistant cells. If the resistance to the antibody is established, other inhibitos of VEGF pathway remain active (such as small molecule nintedanib ) and can inhibit the mTOR pathway. Autocrine VEGF signaling plays a role in CRC cell survival. In subjects resistant to bevacizumab, it would be interesting to introduce the nintedanib alone or in combination to enhance the angiogenic inhibition. Another combination of targeted agents ( anti-VEGF (R) and anti EGFR) has shown efficacy in preclinical models of CRC. The combination of bevacizumab and a small molecule targeting EGFR (erlotinib) showed greater efficacy than bevacizumab alone in CRC models regardless of KRAS status. Bevacizumab induces activation of the EGFR survival pathway in tumor cells and in endothelial cells associated with the tumor. This activation is decreased with the introduction of erlotinib. The results indicate that the combination of bevacizumab and erlotinib are more active in maintenance therapy than bevacizumab alone, even for patients mutated KRAS . These findings led to the positive Phase III clinical study GERCOR DREAM in metastatic colon cancer.

The ErbB family of receptors are key regulators of growth, differentiation, migration and survival of epithelial cells. CI-1033 is an irreversible pan-ErbB tyrosine kinase inhibitor that has the ability to inhibit EGFR function but has shown limited therapeutic efficacy. Lovastatin targets the activity of HMG-CoA reductase, the rate-limiting step in the mevalonate pathway. In this study, the ability of lovastatin to potentiate the cytotoxic effects of CI-1033 was evaluated. The combination of lovastatin and CI-1033 exhibited some cooperative cytotoxic activity in a squamous cell carcinoma–derived cell line. This combination resulted in enhanced cell death by induction of a potent apoptotic response. Furthermore, this drug combination inhibited EGF-induced EGFR autophosphorylation and activation of the downstream signaling effectors, ERK and AKT. These findings suggest that combining lovastatin and tyrosine kinase inhibitors may represent a novel combinational therapeutic approach in squamous cell carcinoma of the head and neck.