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Walz, Thomas M.
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Publications (10 of 24) Show all publications
Kimbung, S., Johansson, I., Danielsson, A., Veerla, S., Egyhazi Brage, S., Frostvik Stolt, M., . . . Hedenfalk, I. (2016). Transcriptional Profiling of Breast Cancer Metastases Identifies Liver Metastasis-Selective Genes Associated with Adverse Outcome in Luminal A Primary Breast Cancer. Clinical Cancer Research, 22(1), 146-157
Open this publication in new window or tab >>Transcriptional Profiling of Breast Cancer Metastases Identifies Liver Metastasis-Selective Genes Associated with Adverse Outcome in Luminal A Primary Breast Cancer
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2016 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 22, no 1, p. 146-157Article in journal (Refereed) Published
Abstract [en]

Purpose: The complete molecular basis of the organ-specificity of metastasis is elusive. This study aimed to provide an independent characterization of the transcriptional landscape of breast cancer metastases with the specific objective to identify liver metastasis-selective genes of prognostic importance following primary tumor diagnosis. Experimental Design: A cohort of 304 women with advanced breast cancer was studied. Associations between the site of recurrence and clinicopathologic features were investigated. Fine-needle aspirates of metastases (n = 91) were subjected to whole-genome transcriptional profiling. Liver metastasis-selective genes were identified by significance analysis of microarray (SAM) analyses and independently validated in external datasets. Finally, the prognostic relevance of the liver metastasis-selective genes in primary breast cancer was tested. Results: Liver relapse was associated with estrogen receptor (ER) expression (P = 0.002), luminal B subtype (P = 0.01), and was prognostic for an inferior postrelapse survival (P = 0.01). The major variation in the transcriptional landscape of metastases was also associated with ER expression and molecular subtype. However, liver metastases displayed unique transcriptional fingerprints, characterized by down-regulation of extracellular matrix (i.e., stromal) genes. Importantly, we identified a 17-gene liver metastasis-selective signature, which was significantly and independently prognostic for shorter relapse-free (P < 0.001) and overall (P = 0.001) survival in ER-positive tumors. Remarkably, this signature remained independently prognostic for shorter relapse-free survival (P = 0.001) among luminal A tumors. Conclusions: Extracellular matrix (stromal) genes can be used to partition breast cancer by site of relapse and may be used to further refine prognostication in ER positive primary breast cancer. (C)2015 AACR.

Place, publisher, year, edition, pages
AMER ASSOC CANCER RESEARCH, 2016
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-124483 (URN)10.1158/1078-0432.CCR-15-0487 (DOI)000367550300018 ()26276891 (PubMedID)
Note

Funding Agencies|Swedish Cancer Society; Swedish Research Council; Gunnar Nilsson Cancer Foundation; Berta Kamprad Foundation; Gyllenstierna Krapperups Foundation; Swedish Cancer and Allergy Foundation; Research Funds at Radiumhemmet; Swedish Breast Cancer Association; ALF/FOU research funds at the Karolinska Institutet; Stockholm County Council; Bristol-Myers Squibb Sweden AB; Pfizer Sweden AB; Roche Sweden AB

Available from: 2016-02-02 Created: 2016-02-01 Last updated: 2017-11-30
Tobin, N. P., Harrell, J. C., Lovrot, J., Egyhazi Brage, S., Frostvik Stolt, M., Carlsson, L., . . . Lindstrom, L. S. (2015). Molecular subtype and tumor characteristics of breast cancer metastases as assessed by gene expression significantly influence patient post-relapse survival. Annals of Oncology, 26(1), 81-88
Open this publication in new window or tab >>Molecular subtype and tumor characteristics of breast cancer metastases as assessed by gene expression significantly influence patient post-relapse survival
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2015 (English)In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 26, no 1, p. 81-88Article in journal (Refereed) Published
Abstract [en]

We and others have recently shown that tumor characteristics are altered throughout tumor progression. These findings emphasize the need for re-examination of tumor characteristics at relapse and have led to recommendations from ESMO and the Swedish Breast Cancer group. Here, we aim to determine whether tumor characteristics and molecular subtypes in breast cancer metastases confer clinically relevant prognostic information for patients. The translational aspect of the Swedish multicenter randomized trial called TEX included 111 patients with at least one biopsy from a morphologically confirmed locoregional or distant breast cancer metastasis diagnosed from December 2002 until June 2007. All patients had detailed clinical information, complete follow-up, and metastasis gene expression information (Affymetrix array GPL10379). We assessed the previously published gene expression modules describing biological processes [proliferation, apoptosis, human epidermal receptor 2 (HER2) and estrogen (ER) signaling, tumor invasion, immune response, and angiogenesis] and pathways (Ras, MAPK, PTEN, AKT-MTOR, PI3KCA, IGF1, Src, Myc, E2F3, and beta-catenin) and the intrinsic subtypes (PAM50). Furthermore, by contrasting genes expressed in the metastases in relation to survival, we derived a poor metastasis survival signature. A significant reduction in post-relapse breast cancer-specific survival was associated with low-ER receptor signaling and apoptosis gene module scores, and high AKT-MTOR, Ras, and beta-catenin module scores. Similarly, intrinsic subtyping of the metastases provided statistically significant post-relapse survival information with the worst survival outcome in the basal-like [hazard ratio (HR) 3.7; 95% confidence interval (CI) 1.3-10.9] and HER2-enriched (HR 4.4; 95% CI 1.5-12.8) subtypes compared with the luminal A subtype. Overall, 25% of the metastases were basal-like, 32% HER2-enriched, 10% luminal A, 28% luminal B, and 5% normal-like. We show that tumor characteristics and molecular subtypes of breast cancer metastases significantly influence post-relapse patient survival, emphasizing that molecular investigations at relapse provide prognostic and clinically relevant information.

Place, publisher, year, edition, pages
Oxford University Press (OUP): Policy A1 - Oxford Open Option F, 2015
Keywords
breast cancer metastases; metastasis characteristics; TEX randomized trial; gene expression; gene modules; biopsy at relapse
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-114243 (URN)10.1093/annonc/mdu498 (DOI)000347416300013 ()25361981 (PubMedID)
Note

Funding Agencies|Swedish Research Council [524-2011-6857, 521-2014-2057]; Swedish Research Council for Health, Working life and Welfare, FORTE [2014-1962]; Swedish Cancer Society; Cancer Society in Stockholm; King Gustaf V Jubilee Foundation; Swedish Breast Cancer Association (BRO); Swedish Research Council; Bristol-Myers Squibb Sweden AB; Pfizer Sweden AB; Roche Sweden AB; NCI Breast SPORE program [P50-CA58223-09A1]; Breast Cancer Research Foundation (CMP)

Available from: 2015-02-16 Created: 2015-02-16 Last updated: 2017-12-04
Suzuki, C., Blomqvist, L., Hatschek, T., Carlsson, L., Einbeigi, Z., Linderholm, B., . . . Glimelius, B. (2013). Impact of the first tumor response at eight weeks on overall survival in metastatic breast cancer patients treated with first-line combination chemotherapy. Medical Oncology, 30(1)
Open this publication in new window or tab >>Impact of the first tumor response at eight weeks on overall survival in metastatic breast cancer patients treated with first-line combination chemotherapy
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2013 (English)In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 30, no 1Article in journal (Refereed) Published
Abstract [en]

The aim of this was to determine whether the change of size observed at the first response evaluation after initiation of first-line combination chemotherapy correlates with overall survival (OS) in patients with metastatic breast cancer (MBC). The change in size of tumors derived from measurements according to Response Evaluation Criteria In Solid Tumors (RECIST) at the first evaluation on computed tomography (CT) was obtained from a multicenter, randomized phase III trial ("TEX trial," n = 287) comparing treatment with a combination of epirubicin and paclitaxel alone or with capecitabine (TEX). Cox regression and Kaplan-Meier analyses were performed to evaluate the correlations between the first change in tumor size, response according to RECIST and OS. Data from CT evaluations of 233 patients were available. Appearance of new lesions or progression of non-target lesions (new/non-target) indicated short OS by univariable regression analysis (HR 3.76, 95 % CI 1.90-7.42, p andlt; 0.001). A decrease by andgt;30 % at this early time point was prognostic favorable (HR 0.69, 95 % CI 0.49-0.98, p = 0.04) and not significantly less than the best overall response according to RECIST. After adjustment for previous adjuvant treatment and the treatment given within the frame of the randomized trial, OS was still significantly shorter in patients with new/non-target lesions after a median 8 weeks of treatment (HR 4.41, 95 % CI 2.74-7.11, p andlt; 0.001). Disease progression at the first evaluation correlates with OS in patients with MBC treated with first-line combination chemotherapy. The main reason for early disease progression was the appearance of new lesions or progression of non-target lesions. These patients had poor OS even though more lines of treatment were available. Thus, these factors should be focused on in the response evaluations besides tumor size changes.

Place, publisher, year, edition, pages
Humana Press, 2013
Keywords
Metastatic breast cancer, Treatment response evaluation, Overall survival, First-line chemotherapy, Computed tomography (CT), RECIST
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-91938 (URN)10.1007/s12032-012-0415-5 (DOI)000316800800093 ()
Note

Funding Agencies|Stockholm country council||Karolinska Institutet||Pfizer||Roche||Sanofi-aventis||

Available from: 2013-05-06 Created: 2013-05-06 Last updated: 2017-12-06
Bjohle, J., Bergqvist, J., Gronowitz, J. S., Johansson, H., Carlsson, L., Einbeigi, Z., . . . Hatschek, T. (2013). Serum thymidine kinase activity compared with CA 15-3 in locally advanced and metastatic breast cancer within a randomized trial. Breast Cancer Research and Treatment, 139(3), 751-758
Open this publication in new window or tab >>Serum thymidine kinase activity compared with CA 15-3 in locally advanced and metastatic breast cancer within a randomized trial
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2013 (English)In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 139, no 3, p. 751-758Article in journal (Refereed) Published
Abstract [en]

The primary objective was to estimate serum thymidine kinase 1 (TK1) activity, reflecting total body cell proliferation rate including cancer cell proliferation, in women with loco regional inoperable or metastatic breast cancer participating in a prospective and randomized study. Secondary objectives were to analyze TK1 in relation to progression-free survival (PFS), overall survival (OS), therapy response and other tumour characteristics, including CA 15-3, widely used as a standard serum marker for disease progression. TK1 and CA 15-3 were analysed in 198 serum samples collected prospectively from women included in the randomized TEX trial between December 2002 and June 2007. TK1 activity was determined by the ELISA based DiviTum (TM) assay, and CA 15-3 analyses was generated with the electrochemiluminescence immunoassay Cobas Elecsys CA 15-3 II. High pre-treatment TK1 activity predicted shorter PFS (10 vs. 15 months p = 0.02) and OS (21 vs. 38 months, p andlt; 0.0001), respectively. After adjustment for age, metastatic site and study treatment TK1 showed a trend as predictor of PFS (p = 0.059) and was an independent prognostic factor for OS, (HR 1.81, 95 % confidence interval (CI) 1.26-2.61, p = 0.001). There was a trend of shortened OS for women with high CA 15-3 (p = 0.054) in univariate analysis, but not after adjustment for the above mentioned covariates. Both TK1 (p = 0.0011) and CA 15-3 (p = 0.0004) predicted response to treatment. There were statistically different distributions of TK1 and CA 15-3 in relation to the site of metastases. TK1 activity measured by DiviTum (TM) predicted therapy response, PFS and OS in loco regional inoperable or disseminated breast cancer. These results suggest that this factor is a useful serum marker. In the present material, a prognostic value of CA 15-3 could not be proven.

Place, publisher, year, edition, pages
Springer Verlag (Germany), 2013
Keywords
TK1, CA 15-3, Breast cancer, Prognostic factor, Predictive factor, DiviTum
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-95969 (URN)10.1007/s10549-013-2579-x (DOI)000321070200012 ()
Note

Funding Agencies|Swedish Cancer Society||Stockholm Cancer Society||King Gustav V Jubilee Fund||Swedish Research Council||Stockholm City Council||Karolinska Institutet||Stockholm County Council Research Strategy Committee||BRECT||Swedish Breast Cancer Association||Marit and Hans Rausings Initiative Against Breast Cancer||Karolinska Institutet Research Funds||Biovica International AB||

Available from: 2013-08-19 Created: 2013-08-12 Last updated: 2017-12-06
Hatschek, T., Carlsson, L., Einbeigi, Z., Lidbrink, E., Linderholm, B., Lindh, B., . . . Bergh, J. (2012). Individually tailored treatment with epirubicin and paclitaxel with or without capecitabine as first-line chemotherapy in metastatic breast cancer: a randomized multicenter trial. Breast Cancer Research and Treatment, 131(3), 939-947
Open this publication in new window or tab >>Individually tailored treatment with epirubicin and paclitaxel with or without capecitabine as first-line chemotherapy in metastatic breast cancer: a randomized multicenter trial
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2012 (English)In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 131, no 3, p. 939-947Article in journal (Refereed) Published
Abstract [en]

Anthracyclines and taxanes are active cytotoxic drugs in the treatment of early metastatic breast cancer. It is yet unclear whether addition of capecitabine to the combination of these drugs improves the treatment outcome. Patients with advanced breast cancer were randomized to first-line chemotherapy with a combination of epirubicin (Farmorubicin(A (R))) and paclitaxel (Taxol(A (R))) alone (ET) or in combination with capecitabine (Xeloda(A (R)), TEX). Starting doses for ET were epirubicin 75 mg/m(2) plus paclitaxel 175 mg/m(2), and for TEX epirubicin 75 mg/m(2), paclitaxel 155 mg/m(2), and capecitabine 825 mg/m(2) BID for 14 days. Subsequently, doses were tailored related to side effects. Primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival (OS), time to treatment failure (TTF), objective response (OR), safety and quality of life (QoL). 287 patients were randomized, 143 to ET and 144 to TEX. Median PFS was 10.8 months for patients treated with ET, and 12.4 months for those treated with TEX (HR 0.84, 95% CI 0.65-1.07, P = 0.16); median OS was 26.0 months for women in the ET versus 29.7 months in the TEX arm (HR 0.84, 95% CI 0.63-1.11, P = 0.22). OR was achieved in 44.8% (ET) and 54.2% (TEX), respectively (chi(2) 3.66, P = 0.16). TTF was significantly longer for patients treated with TEX, 6.0 months, versus 5.2 months following ET (HR 0.73, 95% CI 0.58-0.93, P = 0.009). Severe hematological side effects related to epirubicin and paclitaxel were evenly distributed between the treatment arms, mucositis, diarrhea, and Hand-Foot syndrome were significantly more frequent in the TEX arm. Toxicity-adjusted treatment with ET and TEX showed similar efficacy in terms of PFS, OS, and OR. In this trial with limited power, the addition of capecitabine to epirubicin and paclitaxel as first-line treatment did not translate into clinically relevant improvement of the outcome.

Place, publisher, year, edition, pages
Springer Verlag (Germany), 2012
Keywords
Advanced breast cancer, First-line treatment, Epirubicin, Paclitaxel, Capecitabine
National Category
Social Sciences
Identifiers
urn:nbn:se:liu:diva-74839 (URN)10.1007/s10549-011-1880-9 (DOI)000299346100022 ()
Note
Funding Agencies|Bristol-Myers Squibb Sweden AB||Pfizer Sweden AB||Roche Sweden AB||Research Funds at Radiumhemmet||Swedish Cancer Society||Swedish Breast Cancer Association (BRO)||ALF/FOU at the Karolinska Institutet||Stockholm County Council||Roche||Sanofi-aventis||Available from: 2012-02-10 Created: 2012-02-10 Last updated: 2017-12-07
Djerf Svenningsson, E., Olausson, P., Ghafouri, B., Stål, O., Hallbeck, A.-L. & Walz, T. (2012). Resistance to gefitinib in malignant melanoma cells is related to increased expression of Met and the insulin receptor and sustained Akt signaling.
Open this publication in new window or tab >>Resistance to gefitinib in malignant melanoma cells is related to increased expression of Met and the insulin receptor and sustained Akt signaling
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2012 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: Acquired resistance to cancer therapy, including targeted therapies such as epidermal growth factor receptor (ErbB) tyrosine kinase inhibitors (TKIs), constitutes a major clinical problem in treating patients with malignant disease. Several drug resistance mechanisms for ErbB1 TKIs involving abnormal activation of growth factor receptors or activation of intracellular signaling pathways have been discovered. ErbB TKIs have recently been shown to inhibit growth in melanoma cells. This study was undertaken to develop a gefitinib-resistant melanoma cell line in order to find any resistance mechanism to gefitinib in melanoma cells lacking activating mutation in BRAF or NRAS.

Material and methods: A malignant melanoma cell line (RaH5) was made resistant to the ErbB1 TKI gefitinib by continuous culture with stepwise increasing concentrations of the drug up to 10 μM. The phosphorylation status of 42 different human receptor tyrosine kinases was screened in a protein array in resistant (RaH5ZDR) and wild-type RaH5 cells treated with or without gefitinib. The PI3K, MAPK and Stat3 signaling pathways were studied in an analogous way by Western blot analysis; 2-D gel electrophoresis was performed to determine other potential proteins involved in gefitinib resistance in RaH5 cells. In addition, the effect of the pan-ErbB TKI canertinib on gefitinib-resistant cells was investigated.

Results: Protein array experiments showed that only Met and the insulin receptor (IR) exhibited substantially increased activation in RaH5ZDR cells as compared to their nonresistant counterparts. Interestingly, following gefitinib treatment ErbB2 and ErbB3 receptor signaling in resistant cells were equally well suppressed as in non-resistant cells. However, downstream Akt and Erk1/2 phosphorylation was inhibited to a greater extent in non-resistant RaH5 cells.

Conclusion: Resistance to gefitinib in RaH5 cells appears to be related to an increased expression of Met and IR and linked to a more persistent signaling through Akt and Erk1/2. However, additional studies are required to further elucidate the resistance to gefitinib in our experimental system.

Keywords
Malignant melanoma, gefitinib, canertinib, gefitinib resistance, ErbB, Erk1/2, Akt, Stat3, Met, IR
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-85664 (URN)
Available from: 2012-11-27 Created: 2012-11-27 Last updated: 2012-11-27Bibliographically approved
Nordigården, A., Zetterblad, J., Trinks, C., Green, H., Eliasson, P., Druid, P., . . . Jönsson, J.-I. (2011). Irreversible pan-ERBB inhibitor canertinib elicits anti-leukaemic effects and induces the regression of FLT3-ITD transformed cells in mice. British Journal of Haematology, 155(2), 198-208
Open this publication in new window or tab >>Irreversible pan-ERBB inhibitor canertinib elicits anti-leukaemic effects and induces the regression of FLT3-ITD transformed cells in mice
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2011 (English)In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 155, no 2, p. 198-208Article in journal (Refereed) Published
Abstract [en]

Recent findings have indicated that tyrosine kinase inhibitors (TKIs) targeting the ERBB receptor family display anti-leukaemic effects, despite the lack of receptor expression on human leukaemic cells. The occurrence of activating mutations in the gene encoding FMS-like tyrosine kinase 3 (FLT3) in patients with acute myeloid leukaemia (AML) has rendered inhibition of this receptor a promising therapeutic target. Due to possibility of cross-reactivity, we investigated the effect of the irreversible pan-ERBB inhibitor canertinib (CI-1033) on leukaemic cells expressing FLT3. The drug had anti-proliferative and apoptotic effects on primary AML cells and human leukaemic cell lines expressing mutated FLT3. In several AML patient samples, a blast cell population expressing FLT3-internal tandem duplication (ITD) was eradicated by canertinib. Canertinib inhibited receptor autophosphorylation and kinase activity of both mutated and FLT3 ligand stimulated wildtype FLT3, leading to inhibition of the PI3-kinase and MAP kinase pathways. Apoptotic induction was dependent on pro-apoptotic BH3-only protein BCL2L11/BIM because siRNA silencing attenuated apoptosis. Moreover, the drug induced regression of cells expressing FLT3-ITD in a murine in vivo-transplantation model at previously described tolerated doses. These results indicate that canertinib, as an irreversible TKI, could constitute a novel treatment regimen in patients with mutated or overexpressed FLT3.

Place, publisher, year, edition, pages
Blackwell Publishing, 2011
Keywords
acute myeloid leukaemia, apoptosis, signalling, drugs, murine model, leukaemia therapy
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-72031 (URN)10.1111/j.1365-2141.2011.08819.x (DOI)000296063400006 ()
Note
Funding Agencies|Swedish Cancer Foundation||Swedish Childrens Cancer Foundation||Swedish Research Council||County Council of Ostergotland||Cancer Foundation of Ostergotland||Ollie and Elof Ericssons Foundation||Available from: 2011-11-11 Created: 2011-11-11 Last updated: 2017-12-08
Djerf, E., Trinks, C., Green, H., Abdiu, A., Hallbeck, A.-L., Stål, O. & Walz, T. (2011). The pan-ErbB receptor tyrosine kinase inhibitor canertinib promotes apoptosis of malignant melanoma in vitro and displays anti-tumor activity in vivo. Biochemical and Biophysical Research Communications - BBRC, 414(3), 563-568
Open this publication in new window or tab >>The pan-ErbB receptor tyrosine kinase inhibitor canertinib promotes apoptosis of malignant melanoma in vitro and displays anti-tumor activity in vivo
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2011 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 414, no 3, p. 563-568Article in journal (Refereed) Published
Abstract [en]

The ErbB receptor family has been suggested to constitute a therapeutic target for tumor-specific treatment of malignant melanoma. Here we investigate the effect of the pan-ErbB tyrosine kinase inhibitor canertinib on cell growth and survival in human melanoma cells in vitro and in vivo. Canertinib significantly inhibited growth of cultured melanoma cells, RaH3 and RaH5, in a dose-dependent manner as determined by cell counting. Half-maximum growth inhibitory dose (IC(50)) was approximately 0.8 mu M and by 5 mu M both cell lines were completely growth-arrested within 72 h of treatment. Incubation of exponentially growing RaH3 and RaH5 with 1 mu M canertinib accumulated the cells in the G(1)-phase of the cell cycle within 24 h of treatment without induction of apoptosis as determined by flow cytometry. Immunoblot analysis showed that 1 mu M canertinib inhibited ErbB1-3 receptor phosphorylation with a concomitant decrease of Akt-, Erk1/2- and Stat3 activity in both cell lines. In contrast to the cytostatic effect observed at doses less than= 5 mu M canertinib, higher concentrations induced apoptosis as demonstrated by the Annexin V method and Western blot analysis of PARP cleavage. Furthermore, canertinib significantly inhibited growth of RaH3 and RaH5 melanoma xenografts in nude mice. Pharmacological targeting of the ErbB receptors may prove successful in the treatment of patients with metastatic melanoma.

Place, publisher, year, edition, pages
Elsevier, 2011
Keywords
Malignant melanoma; Tyrosine kinase inhibitor; Canertinib; ErbB-receptor; Apoptosis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-73740 (URN)10.1016/j.bbrc.2011.09.118 (DOI)000298519500021 ()
Note

On the day of the defence date the status of this article was Manuscript and the title "The pan-ErbB receptor tyrosine kinase inhibitor Canertinib (CI-1033)promotes cell cycle arrest and apoptosis of human malignantmelanoma in vitro".

Available from: 2012-01-12 Created: 2012-01-12 Last updated: 2017-12-08
Trinks, C., Severinsson, E. A., Holmlund, B., Gréen, A., Green, H., Jönsson, J.-I., . . . Walz, T. (2011). The pan-ErbB tyrosine kinase inhibitor canertinib induces caspase-mediated cell death in human T-cell leukemia (Jurkat) cells. Biochemical and Biophysical Research Communications - BBRC, 410(3), 422-427
Open this publication in new window or tab >>The pan-ErbB tyrosine kinase inhibitor canertinib induces caspase-mediated cell death in human T-cell leukemia (Jurkat) cells
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2011 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 410, no 3, p. 422-427Article in journal (Refereed) Published
Abstract [en]

Canertinib is a novel ErbB-receptor inhibitor currently in clinical development for the treatment of solid tumors overexpressing ErbB-receptors. We have recently demonstrated that canertinib displays anti-proliferative and pro-apoptotic effects in human myeloid leukemia cells devoid of ErbB-receptors. The mechanism mediating these effects are however unknown. In this study, we show that canertinib is able to act as a multi-kinase inhibitor by inhibition of several intracellular kinases involved in T-cell signaling such as Akt, Erk1/2 and Zap-70, and reduced Lck protein expression in the human T-cell leukemia cell line Jurkat. Treatment with canertinib at a concentration of 2 mu M caused accumulation of Jurkat cells in the G(1) cell cycle phase and increased doses induced apoptosis in a time-dependent manner. Apoptotic signs of treated cells were detected by Annexin V staining and cleavage of PARP, caspase-3, -8, -9, -10 and Bid. A subset of the pro-apoptotic signals mediated by canertinib could be significantly reduced by specific caspase inhibitors. Taken together, these results demonstrate the dual ability of canertinib to downregulate important signaling pathways and to activate caspase-mediated intrinsic apoptosis pathway in human T-cell leukemia cells.

Place, publisher, year, edition, pages
Elsevier Science B.V., Amsterdam, 2011
Keywords
T-cell leukemia; Canertinib; ErbB-receptor; Apoptosis; Caspase; Intracellular signaling
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-69797 (URN)10.1016/j.bbrc.2011.05.148 (DOI)000292797700009 ()
Available from: 2011-08-10 Created: 2011-08-08 Last updated: 2017-12-08
Hatschek, T., Einbeigi, Z., Walz, T., Malmberg, M., Loman, N., Carlsson, L., . . . Sundqvist, M. (2010). Individually dose-adjusted treatment with epirubicin and paclitaxel with or without capecitabine as 1st line treatment in metastatic breast cancer. A randomized multicenter trial in EJC SUPPLEMENTS, vol 8, issue 3, pp 195-196. In: EJC SUPPLEMENTS (pp. 195-196). Elsevier Science B.V., Amsterdam., 8(3)
Open this publication in new window or tab >>Individually dose-adjusted treatment with epirubicin and paclitaxel with or without capecitabine as 1st line treatment in metastatic breast cancer. A randomized multicenter trial in EJC SUPPLEMENTS, vol 8, issue 3, pp 195-196
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2010 (English)In: EJC SUPPLEMENTS, Elsevier Science B.V., Amsterdam. , 2010, Vol. 8, no 3, p. 195-196Conference paper, Published paper (Refereed)
Abstract [en]

n/a

Place, publisher, year, edition, pages
Elsevier Science B.V., Amsterdam., 2010
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-58652 (URN)000276756900486 ()
Available from: 2010-08-22 Created: 2010-08-20 Last updated: 2010-08-22
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