John B A G Haanen

Netherlands Cancer Institute, Amsterdamo, North Holland, Netherlands

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Publications (153)1341.54 Total impact

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    ABSTRACT: Cellular immunity against cancer can be achieved with viral vector- and DNA-based immunizations. In preclinical studies cancer vaccines are very potent, but in clinical trials these potencies are not achieved yet. Thus a rational approach to improve cancer vaccines is warranted. We previously demonstrated that the relatively low intrinsic immunogenicity of DNA vaccines could be enhanced by inclusion of endoplasmic reticulum (ER) targeting and universal helper epitopes within the vaccine. We now evaluated whether an optimal antigen format, as defined in DNA vaccines can further enhance the effectiveness of recombinant Semliki Forest virus (rSFV) vaccines. To this purpose, we generated, characterized and evaluated the efficacy of rSFV replicon particles expressing human papilloma virus E6 and/or E7 proteins fused to several helper T cell epitopes and an ER targeting signal. Here we show that inclusion of a helper cassette and an ER targeting signal enhanced protein stability and markedly augmented the frequencies of HPV-specific T cells. Even at an immunization dose of as low as 10(5) replicon particles this novel vaccine achieved tumor regression and protection. Thus, even highly effective viral vector vaccines can benefit from an improved antigen format, based on the inclusion of defined helper epitopes and ER targeting.Gene Therapy accepted article preview online, 10 March 2015. doi:10.1038/gt.2015.24.
    Gene Therapy 03/2015; DOI:10.1038/gt.2015.24 · 4.20 Impact Factor
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    ABSTRACT: Selective BRAF inhibition (BRAFi) by vemurafenib or dabrafenib has become approved standard treatment in BRAF V600 mutated advanced stage melanoma. While the response rate is high, the response duration is limited with a progression-free survival (PFS) of 5-6months. Our observation of accelerated disease progression within some patients after stopping vemurafenib treatment has fostered the idea of treatment beyond progression (BRAFi TBP). In this retrospective study, we analysed 70 metastatic melanoma patients, treated at our institute, who experienced progression after prior objective response upon treatment with vemurafenib. Thirty-five patients that continued treatment beyond progression are compared with 35 patients who stopped BRAFi treatment at disease progression. Median overall survival beyond documented progression was found to be 5.2months versus 1.4months (95% confidence interval (CI): 3.8-7.4 versus 0.6-3.4; Log-Rank p=0.002) in favour of BRAFi TBP. In the multivariate survival analysis, stopping treatment at disease progression was significantly associated with shorter survival (hazard ratio: 1.92; 95% CI: 1.04-3.55; p=0.04). Our results suggest that continuing vemurafenib treatment beyond progression may be beneficial in advanced melanoma patients, who prior to progression responded to vemurafenib. Copyright © 2015 Elsevier Ltd. All rights reserved.
    European journal of cancer (Oxford, England: 1990) 02/2015; 51(5). DOI:10.1016/j.ejca.2015.01.009 · 4.82 Impact Factor
  • John B.A.G. Haanen, Hans van Thienen, Christian U. Blank
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    ABSTRACT: Immune checkpoint molecules CTLA4 and PD1, but also LAG-3 and TIM-3 are involved in regulation of peripheral tolerance in order to prevent autoimmunity. Blocking of these cell surface proteins by blocking antibodies has resulted in remarkable antitumor immunity, however is accompanied by immune related adverse reactions, resembling autoimmune diseases. Hence, treatment with immunosuppressive drugs is highly effective and resolves the symptoms caused by these adverse events rapidly.
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    ABSTRACT: Tumor-specific neo-antigens that arise as a consequence of mutations are thought to be important for the therapeutic efficacy of cancer immunotherapies. Accumulating evidence suggests that neo-antigens may be commonly recognized by intratumoral CD8+ T cells, but it is unclear whether neo-antigen-specific CD4+ T cells also frequently reside within human tumors. In view of the accepted role of tumor-specific CD4+ T-cell responses in tumor control, we addressed whether neo-antigen-specific CD4+ T-cell reactivity is a common property in human melanoma.
    Nature Medicine 12/2014; DOI:10.1038/nm.3773 · 28.05 Impact Factor
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    ABSTRACT: After an infection, pathogen-specific tissue-resident memory T cells (T(RM) cells) persist in nonlymphoid tissues to provide rapid control upon reinfection, and vaccination strategies that create T(RM) cell pools at sites of pathogen entry are therefore attractive. However, it is not well understood how T(RM) cells provide such pathogen protection. Here, we demonstrate that activated T(RM) cells in mouse skin profoundly alter the local tissue environment by inducing a number of broadly active antiviral and antibacterial genes. This "pathogen alert" allows skin T(RM) cells to protect against an antigenically unrelated virus. These data describe a mechanism by which tissue-resident memory CD8(+) T cells protect previously infected sites that is rapid, amplifies the activation of a small number of cells into an organ-wide response, and has the capacity to control escape variants.
    Science 10/2014; 346(6205):101-5. DOI:10.1126/science.1254803 · 31.48 Impact Factor
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    ABSTRACT: Background Combined BRAF and MEK inhibition, as compared with BRAF inhibition alone, delays the emergence of resistance and reduces toxic effects in patients who have melanoma with BRAF V600E or V600K mutations. Methods In this phase 3 trial, we randomly assigned 423 previously untreated patients who had unresectable stage IIIC or stage IV melanoma with a BRAF V600E or V600K mutation to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily) or dabrafenib and placebo. The primary end point was progression-free survival. Secondary end points included overall survival, response rate, response duration, and safety. A preplanned interim overall survival analysis was conducted. Results The median progression-free survival was 9.3 months in the dabrafenib-trametinib group and 8.8 months in the dabrafenib-only group (hazard ratio for progression or death in the dabrafenib-trametinib group, 0.75; 95% confidence interval [CI], 0.57 to 0.99; P=0.03). The overall response rate was 67% in the dabrafenib-trametinib group and 51% in the dabrafenib-only group (P=0.002). At 6 months, the interim overall survival rate was 93% with dabrafenib-trametinib and 85% with dabrafenib alone (hazard ratio for death, 0.63; 95% CI, 0.42 to 0.94; P=0.02). However, a specified efficacy-stopping boundary (two-sided P=0.00028) was not crossed. Rates of adverse events were similar in the two groups, although more dose modifications occurred in the dabrafenib-trametinib group. The rate of cutaneous squamous-cell carcinoma was lower in the dabrafenib-trametinib group than in the dabrafenib-only group (2% vs. 9%), whereas pyrexia occurred in more patients (51% vs. 28%) and was more often severe (grade 3, 6% vs. 2%) in the dabrafenib-trametinib group. Conclusions A combination of dabrafenib and trametinib, as compared with dabrafenib alone, improved the rate of progression-free survival in previously untreated patients who had metastatic melanoma with BRAF V600E or V600K mutations. (Funded by GlaxoSmithKline; Clinical Trials.gov number, NCT01584648 .).
    New England Journal of Medicine 09/2014; DOI:10.1056/NEJMoa1406037 · 54.42 Impact Factor
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    ABSTRACT: Anti-CTLA-4 treatment improves the survival of patients with advanced-stage melanoma. However, although the anti-CTLA-4 antibody ipilimumab is now an approved treatment for patients with metastatic disease, it remains unknown by which mechanism it boosts tumor-specific T cell activity. In particular, it is unclear whether treatment amplifies previously induced T cell responses or whether it induces new tumor-specific T cell reactivities. Using a combination ultraviolet (UV)-induced peptide exchange and peptide-major histocompatibility complex (pMHC) combinatorial coding, we monitored immune reactivity against a panel of 145 melanoma-associated epitopes in a cohort of patients receiving anti-CTLA-4 treatment. Comparison of pre- and posttreatment T cell reactivities in peripheral blood mononuclear cell samples of 40 melanoma patients demonstrated that anti-CTLA-4 treatment induces a significant increase in the number of detectable melanoma-specific CD8 T cell responses (P = 0.0009). In striking contrast, the magnitude of both virus-specific and melanoma-specific T cell responses that were already detected before start of therapy remained unaltered by treatment (P = 0.74). The observation that anti-CTLA-4 treatment induces a significant number of newly detected T cell responses-but only infrequently boosts preexisting immune responses-provides strong evidence for anti-CTLA-4 therapy-enhanced T cell priming as a component of the clinical mode of action.
    Science translational medicine 09/2014; 6(254-254):254ra128. DOI:10.1126/scitranslmed.3008918 · 14.41 Impact Factor
  • Sander Kelderman, Ton N. M. Schumacher, John B.A.G. Haanen
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    ABSTRACT: A number of immunotherapies, in particular immune checkpoint targeting antibodies and adoptive T-cell therapies, are starting to transform the treatment of advanced cancers. The likelihood to respond to these immunotherapies differs strongly across tumor types, with response rates for checkpoint targeting being the highest in advanced melanoma, renal cell cancer and non-small cell lung cancer. However, also non-responsiveness is observed, indicating the presence of intrinsic resistance or naturally acquired resistance. In addition, a subgroup of patients that do initially respond to immunotherapy will later recur, thereby also pointing towards a role of therapy-induced acquired resistance. Here, we review our current understanding of both intrinsic and acquired resistance mechanisms in cancer immunotherapy, and discuss potential strategies to overcome them.
    Molecular Oncology 09/2014; 8(6). DOI:10.1016/j.molonc.2014.07.011 · 5.94 Impact Factor
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    ABSTRACT: Advances in genetic engineering have made it possible to generate human T cell products that carry desired functionalities, such as the ability to recognize cancer cells. The currently used strategies for the generation of gene-modified T cell products lead to highly differentiated cells within the infusion product, and on the basis of data obtained in preclinical models, this is likely to impact the efficacy of these products. We set out to develop a Good Manufacturing Practice (GMP) protocol that yields TCR gene modified T cells with more favourably properties for clinical application. Here, we show the robust clinical scale production of human peripheral blood T cells with an early memory phenotype that express a MART-1-specific T cell receptor. By combining selection and stimulation using anti-CD3/CD28 beads for retroviral transduction, followed by expansion in the presence of IL-7 and IL-15, production of a well-defined clinical scale TCR gene modified T cell product could be achieved. A major fraction of the T cells generated in this fashion were shown to co-express CD62L and CD45RA, and express CD27 and CD28 indicating a central memory or memory stem-like phenotype. Furthermore, these cells produced IFNγ, TNFα and IL-2, and displayed cytolytic activity against target cells expressing the relevant antigen. The T cell products manufactured by this robust and validated GMP production process are now undergoing testing in a phase I/IIa clinical trial in HLA-A*02:01 - MART-1 positive advanced stage melanoma patients. To our knowledge, this is the first clinical trial protocol in which the combination of IL-7 and IL-15 has been applied for the generation of gene-modified T cell products.
    Human Gene Therapy Methods 08/2014; DOI:10.1089/hgtb.2014.004 · 1.64 Impact Factor
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    ABSTRACT: In this study, we investigated a large series of immune (escape) markers, relevant to T-cell function, as potential biomarkers for clinical outcome following immunotherapy. We retrospectively studied the expression of immune (escape) markers in metastatic melanoma tissues of 27 patients before autologous tumor cell vaccination, and 16 patients who were intended to treat but were not vaccinated because of rapid disease progression. Immunohistochemical data of infiltrating (suppressive) cells, such as T cells, regulatory T cells, myeloid-derived suppressor cells, and mast cells, or the expression of T-cell inhibitory factors (PD-1/PD-L1, IDO, and galectins), cytotoxic molecules (granzyme-B), melanocyte differentiation antigens, HLA class-I and tolerogenic cytokines [interleukin (IL)-1, IL-6, IL-10, TNF-α, and TGF-β] were correlated statistically to clinical outcome and overall survival (OS). Significantly more tumor-infiltrating CD4(+) and CD8(+) T cells (both P < 0.05) were found in nonprogressors to vaccination (n = 9; median OS, 56 months), compared with progressors (n = 18; median OS, 9.5 months). Moreover, granzyme-B expression was elevated in the tumors of nonprogressors, suggesting activated cytotoxic T cells or natural killer cells. T-cell infiltration and granzyme-B expression significantly correlated with overall OS. T-cell inhibitory factors and suppressive cells did not correlate with OS, suggesting minor influence of these immune-escape markers on clinical outcome. The data of progressors were comparable with those from patients with rapid progression (not vaccinated; n = 16; median OS, 3 months). Our study shows that high numbers of intratumoral activated CD4(+) or CD8(+) T cells, before autologous tumor cell vaccination, are associated with favorable clinical outcome. Analyses of these markers in the patients' tumor tissues before immunotherapy may therefore be a valuable tool to select patients for whom the treatment may result in potential clinical benefit. Cancer Immunol Res; 2(6); 538-46. ©2014 AACR.
    06/2014; 2(6):538-46. DOI:10.1158/2326-6066.CIR-13-0097
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    ABSTRACT: Background:Plasma exposure of sunitinib shows large inter-individual variation. Therefore, a pharmacokinetic (PK) study was performed to determine safety and feasibility of sunitinib dosing based on PK levels.Methods:Patients were treated with sunitinib 37.5 mg once daily. At days 15 and 29 of treatment, plasma trough levels of sunitinib and N-desethyl sunitinib were measured. If the total trough level (TTL) was <50 ng ml(-1) and the patient did not show any grade 3 toxicity, the daily sunitinib dose was increased by 12.5 mg. If the patient suffered from grade 3 toxicity, the sunitinib dose was lowered by 12.5 mg.Results:Twenty-nine out of 43 patients were evaluable for PK assessments. Grade 3 adverse events were experienced in seven patients (24%) at the starting dose and in nine patients (31%) after dose escalation. TTLs were below target in 15 patients (52%) at the starting dose. Of these, five patients (17%) reached target TTL after dose escalation without additional toxicity.Conclusions:In a third of the patients that were below target TTL at standard dose, the sunitinib dose could be increased without additional toxicities. This could be the basis for future studies and the implementation of a PK-guided dosing strategy in clinical practice.British Journal of Cancer advance online publication, 15 April 2014; doi:10.1038/bjc.2014.194 www.bjcancer.com.
    British Journal of Cancer 04/2014; DOI:10.1038/bjc.2014.194 · 4.82 Impact Factor
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    ABSTRACT: Treatment of BRAF(V600E) mutant melanoma by small molecule drugs that target the BRAF or MEK kinases can be effective, but resistance develops invariably1, 2. In contrast, colon cancers that harbour the same BRAF(V600E) mutation are intrinsically resistant to BRAF inhibitors, due to feedback activation of the epidermal growth factor receptor (EGFR)3, 4. Here we show that 6 out of 16 melanoma tumours analysed acquired EGFR expression after the development of resistance to BRAF or MEK inhibitors. Using a chromatin-regulator-focused short hairpin RNA (shRNA) library, we find that suppression of sex determining region Y-box 10 (SOX10) in melanoma causes activation of TGF-β signalling, thus leading to upregulation of EGFR and platelet-derived growth factor receptor-β (PDGFRB), which confer resistance to BRAF and MEK inhibitors. Expression of EGFR in melanoma or treatment with TGF-β results in a slow-growth phenotype with cells displaying hallmarks of oncogene-induced senescence. However, EGFR expression or exposure to TGF-β becomes beneficial for proliferation in the presence of BRAF or MEK inhibitors. In a heterogeneous population of melanoma cells having varying levels of SOX10 suppression, cells with low SOX10 and consequently high EGFR expression are rapidly enriched in the presence of drug, but this is reversed when the drug treatment is discontinued. We find evidence for SOX10 loss and/or activation of TGF-β signalling in 4 of the 6 EGFR-positive drug-resistant melanoma patient samples. Our findings provide a rationale for why some BRAF or MEK inhibitor-resistant melanoma patients may regain sensitivity to these drugs after a ‘drug holiday’ and identify patients with EGFR-positive melanoma as a group that may benefit from re-treatment after a drug holiday.
    Nature 04/2014; 508(7494):118-22. DOI:10.1038/nature13121 · 42.35 Impact Factor
  • European Urology Supplements 04/2014; 13(1):e1137. DOI:10.1016/S1569-9056(14)61117-9 · 3.37 Impact Factor
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    ABSTRACT: Ipilimumab, a cytotoxic T lymphocyte-associated antigen-4 blocking antibody, has improved overall survival (OS) in metastatic melanoma in phase III trials. However, about 80 % of patients fail to respond, and no predictive markers for benefit from therapy have been identified. We analysed a 'real world' population of patients treated with ipilimumab to identify markers for treatment benefit. Patients with advanced cutaneous melanoma were treated in the Netherlands (NL) and the United Kingdom (UK) with ipilimumab at 3 mg/kg. Baseline characteristics and peripheral blood parameters were assessed, and patients were monitored for the occurrence of adverse events and outcomes. A total of 166 patients were treated in the Netherlands. Best overall response and disease control rates were 17 and 35 %, respectively. Median follow-up was 17.9 months, with a median progression-free survival of 2.9 months. Median OS was 7.5 months, and OS at 1 year was 37.8 % and at 2 years was 22.9 %. In a multivariate model, baseline serum lactate dehydrogenase (LDH) was demonstrated to be the strongest predictive factor for OS. These findings were validated in an independent cohort of 64 patients from the UK. In both the NL and UK cohorts, long-term benefit of ipilimumab treatment was unlikely for patients with baseline serum LDH greater than twice the upper limit of normal. In the absence of prospective data, clinicians treating melanoma may wish to consider the data presented here to guide patient selection for ipilimumab therapy.
    Cancer Immunology and Immunotherapy 03/2014; DOI:10.1007/s00262-014-1528-9 · 3.94 Impact Factor
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    ABSTRACT: Methods Patients with advanced cutaneous melanoma were treated in the netherlands (nl) and the United King-dom (UK) with ipilimumab at 3 mg/kg. Baseline charac-teristics and peripheral blood parameters were assessed, and patients were monitored for the occurrence of adverse events and outcomes. Results a total of 166 patients were treated in the neth-erlands. Best overall response and disease control rates were 17 and 35 %, respectively. Median follow-up was 17.9 months, with a median progression-free survival of 2.9 months. Median OS was 7.5 months, and OS at 1 year was 37.8 % and at 2 years was 22.9 %. In a multivariate model, baseline serum lactate dehydrogenase (lDH) was demonstrated to be the strongest predictive factor for OS. Abstract Introduction Ipilimumab, a cytotoxic t lymphocyte-associated antigen-4 blocking antibody, has improved over-all survival (OS) in metastatic melanoma in phase III tri-als. However, about 80 % of patients fail to respond, and no predictive markers for benefit from therapy have been identified. We analysed a 'real world' population of patients treated with ipilimumab to identify markers for treatment benefit.
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    ABSTRACT: Methods Patients with advanced cutaneous melanoma were treated in the netherlands (nl) and the United King-dom (UK) with ipilimumab at 3 mg/kg. Baseline charac-teristics and peripheral blood parameters were assessed, and patients were monitored for the occurrence of adverse events and outcomes. Results a total of 166 patients were treated in the neth-erlands. Best overall response and disease control rates were 17 and 35 %, respectively. Median follow-up was 17.9 months, with a median progression-free survival of 2.9 months. Median OS was 7.5 months, and OS at 1 year was 37.8 % and at 2 years was 22.9 %. In a multivariate model, baseline serum lactate dehydrogenase (lDH) was demonstrated to be the strongest predictive factor for OS. Abstract Introduction Ipilimumab, a cytotoxic t lymphocyte-associated antigen-4 blocking antibody, has improved over-all survival (OS) in metastatic melanoma in phase III tri-als. However, about 80 % of patients fail to respond, and no predictive markers for benefit from therapy have been identified. We analysed a 'real world' population of patients treated with ipilimumab to identify markers for treatment benefit.
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    ABSTRACT: In the BRIM-3 trial, vemurafenib was associated with risk reduction versus dacarbazine of both death and progression in patients with advanced BRAF(V600) mutation-positive melanoma. We present an extended follow-up analysis of the total population and in the BRAF(V600E) and BRAF(V600K) mutation subgroups. Patients older than 18 years, with treatment-naive metastatic melanoma and whose tumour tissue was positive for BRAF(V600) mutations were eligible. Patients also had to have a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate haematological, hepatic, and renal function. Patients were randomly assigned by interactive voice recognition system to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg/m(2) of body surface area intravenously every 3 weeks). Coprimary endpoints were overall survival and progression-free survival, analysed in the intention-to-treat population (n=675), with data censored at crossover. A sensitivity analysis was done. This trial is registered with ClinicalTrials.gov, NCT01006980. 675 eligible patients were enrolled from 104 centres in 12 countries between Jan 4, 2010, and Dec 16, 2010. 337 patients were randomly assigned to receive vemurafenib and 338 to receive dacarbazine. Median follow-up was 12·5 months (IQR 7·7-16·0) on vemurafenib and 9·5 months (3·1-14·7) on dacarbazine. 83 (25%) of the 338 patients initially randomly assigned to dacarbazine crossed over from dacarbazine to vemurafenib. Median overall survival was significantly longer in the vemurafenib group than in the dacarbazine group (13·6 months [95% CI 12·0-15·2] vs 9·7 months [7·9-12·8]; hazard ratio [HR] 0·70 [95% CI 0·57-0·87]; p=0·0008), as was median progression-free survival (6·9 months [95% CI 6·1-7·0] vs 1·6 months [1·6-2·1]; HR 0·38 [95% CI 0·32-0·46]; p<0·0001). For the 598 (91%) patients with BRAF(V600E) disease, median overall survival in the vemurafenib group was 13·3 months (95% CI 11·9-14·9) compared with 10·0 months (8·0-14·0) in the dacarbazine group (HR 0·75 [95% CI 0·60-0·93]; p=0·0085); median progression-free survival was 6·9 months (95% CI 6·2-7·0) and 1·6 months (1·6-2·1), respectively (HR 0·39 [95% CI 0·33-0·47]; p<0·0001). For the 57 (9%) patients with BRAF(V600K) disease, median overall survival in the vemurafenib group was 14·5 months (95% CI 11·2-not estimable) compared with 7·6 months (6·1-16·6) in the dacarbazine group (HR 0·43 [95% CI 0·21-0·90]; p=0·024); median progression-free survival was 5·9 months (95% CI 4·4-9·0) and 1·7 months (1·4-2·9), respectively (HR 0·30 [95% CI 0·16-0·56]; p<0·0001). The most frequent grade 3-4 events were cutaneous squamous-cell carcinoma (65 [19%] of 337 patients) and keratoacanthomas (34 [10%]), rash (30 [9%]), and abnormal liver function tests (38 [11%]) in the vemurafenib group and neutropenia (26 [9%] of 287 patients) in the dacarbazine group. Eight (2%) patients in the vemurafenib group and seven (2%) in the dacarbazine group had grade 5 events. Inhibition of BRAF with vemurafenib improves survival in patients with the most common BRAF(V600E) mutation and in patients with the less common BRAF(V600K) mutation. F Hoffmann-La Roche-Genentech.
    The Lancet Oncology 02/2014; DOI:10.1016/S1470-2045(14)70012-9 · 24.73 Impact Factor
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    ABSTRACT: Increased expression of the Microphthalmia-associated transcription factor (MITF) contributes to melanoma progression and resistance to BRAF pathway inhibition. Here we show that the lack of MITF is associated with more severe resistance to a range of inhibitors, while its presence is required for robust drug responses. Both in primary and acquired resistance, MITF levels inversely correlate with the expression of several activated receptor tyrosine kinases, most frequently AXL. The MITF-low/AXL-high/drug-resistance phenotype is common among mutant BRAF and NRAS melanoma cell lines. The dichotomous behaviour of MITF in drug response is corroborated in vemurafenib-resistant biopsies, including MITF-high and -low clones in a relapsed patient. Furthermore, drug cocktails containing AXL inhibitor enhance melanoma cell elimination by BRAF or ERK inhibition. Our results demonstrate that a low MITF/AXL ratio predicts early resistance to multiple targeted drugs, and warrant clinical validation of AXL inhibitors to combat resistance of BRAF and NRAS mutant MITF-low melanomas.
    Nature Communications 01/2014; 5:5712. DOI:10.1038/ncomms6712 · 10.74 Impact Factor

Publication Stats

8k Citations
1,341.54 Total Impact Points

Institutions

  • 1999–2015
    • Netherlands Cancer Institute
      • • Department of Medical Oncology
      • • Department of Urology
      • • Division of Immunology
      Amsterdamo, North Holland, Netherlands
  • 2011
    • University of Amsterdam
      Amsterdamo, North Holland, Netherlands
    • Massachusetts General Hospital
      Boston, Massachusetts, United States
  • 2008–2010
    • VU University Medical Center
      Amsterdamo, North Holland, Netherlands
  • 2009
    • Slotervaartziekenhuis
      Amsterdamo, North Holland, Netherlands
  • 2005
    • Johns Hopkins University
      Baltimore, Maryland, United States