Xiaowei Xu

University of Pennsylvania, Filadelfia, Pennsylvania, United States

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Publications (117)697.04 Total impact

  • Cancer Research 08/2015; 75(15 Supplement):687-687. DOI:10.1158/1538-7445.AM2015-687 · 9.28 Impact Factor
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    ABSTRACT: Resistance to BRAF inhibitors (BRAFi) is one of the major challenges for targeted therapies for BRAF mutant melanomas. However, little is known about the role of microRNAs in conferring BRAFi-resistance. Herein, we demonstrate that miR-200c expression is significantly reduced whereas miR-200c target genes including Bmi1, Zeb2, Tubb3, ABCG5 and MDR1 are significantly increased in melanomas that acquired BRAFi resistance compared to pre-treatment tumor biopsies. Similar changes were observed in BRAFi-resistant melanoma cell lines. Overexpression of miR-200c or knockdown of Bmi1 in resistant melanoma cells restores their sensitivities to BRAFi, leading to deactivation of the PI3K/AKT and MAPK signaling cascades, and acquisition of epithelial-mesenchymal transition-like phenotypes, including up-regulation of E-cadherin, down-regulation of N-cadherin, and ABCG5 and MDR1 expression. Conversely, knockdown of miR-200c or overexpression of Bmi1 in BRAFi-sensitive melanoma cells activates the PI3K/AKT and MAPK pathways, upregulates N-cadherin, ABCG5 and MDR1 expression, and downregulation of E-cadherin expression, leading to BRAFi-resistance. Together, our data identify miR-200c as a critical signaling node in BRAFi-resistant melanomas impacting the MAPK and PI3K/AKT pathways, suggesting miR-200c as a potential therapeutic target for overcoming acquired BRAFi resistance. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Pigment Cell & Melanoma Research 04/2015; 28(4). DOI:10.1111/pcmr.12379 · 5.64 Impact Factor
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    ABSTRACT: Circulating tumor cell (CTC) detection and genetic analysis may complement currently available disease assessments in patients with melanoma to improve risk stratification and monitoring. We therefore sought to establish the feasibility of a telomerase-based assay for detecting and isolating live melanoma CTCs. The telomerase-based CTC assay utilizes an adenoviral vector that, in the presence of elevated human telomerase activity, drives the amplification of green fluorescent protein. Tumor cells are then identified via an image processing system. The protocol was tested on melanoma cells in culture or spiked into control blood, and on samples from patients with metastatic melanoma. Genetic analysis of the isolated melanoma CTCs was then performed for BRAF mutation status. The adenoviral vector was effective for all melanoma cell lines tested with sensitivity of 88.7% (95%CI 85.6-90.4%) and specificity of 99.9% (95%CI 99.8-99.9%). In a pilot trial of patients with metastatic disease, CTCs were identified in 9 of 10 patients, with a mean of 6.0 CTCs/mL. At a cutoff of 1.1 CTCs/mL, the telomerase-based assay exhibits test performance of 90.0% sensitivity and 91.7% specificity. BRAF mutation analysis of melanoma cells isolated from culture or spiked control blood, or from pilot patient samples was found to match the known BRAF mutation status of the cell lines and primary tumors. To our knowledge, this is the first report of a telomerase-based assay effective for detecting and isolating live melanoma CTCs. These promising findings support further studies, including towards integrating into the management of patients with melanoma receiving multimodality therapy.
    PLoS ONE 03/2015; 10(3):e0123376. DOI:10.1371/journal.pone.0123376 · 3.23 Impact Factor
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    ABSTRACT: Immune checkpoint inhibitors result in impressive clinical responses, but optimal results will require combination with each other and other therapies. This raises fundamental questions about mechanisms of non-redundancy and resistance. Here we report major tumour regressions in a subset of patients with metastatic melanoma treated with an anti-CTLA4 antibody (anti-CTLA4) and radiation, and reproduced this effect in mouse models. Although combined treatment improved responses in irradiated and unirradiated tumours, resistance was common. Unbiased analyses of mice revealed that resistance was due to upregulation of PD-L1 on melanoma cells and associated with T-cell exhaustion. Accordingly, optimal response in melanoma and other cancer types requires radiation, anti-CTLA4 and anti-PD-L1/PD-1. Anti-CTLA4 predominantly inhibits T-regulatory cells (Treg cells), thereby increasing the CD8 T-cell to Treg (CD8/Treg) ratio. Radiation enhances the diversity of the T-cell receptor (TCR) repertoire of intratumoral T cells. Together, anti-CTLA4 promotes expansion of T cells, while radiation shapes the TCR repertoire of the expanded peripheral clones. Addition of PD-L1 blockade reverses T-cell exhaustion to mitigate depression in the CD8/Treg ratio and further encourages oligoclonal T-cell expansion. Similarly to results from mice, patients on our clinical trial with melanoma showing high PD-L1 did not respond to radiation plus anti-CTLA4, demonstrated persistent T-cell exhaustion, and rapidly progressed. Thus, PD-L1 on melanoma cells allows tumours to escape anti-CTLA4-based therapy, and the combination of radiation, anti-CTLA4 and anti-PD-L1 promotes response and immunity through distinct mechanisms.
    Nature 03/2015; 520(7547). DOI:10.1038/nature14292 · 42.35 Impact Factor
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    ABSTRACT: Direct reprogramming provides a fundamentally new approach for the generation of patient-specific cells. Here, by screening a pool of candidate transcription factors, we identify that a combination of the three factors, MITF, SOX10 and PAX3, directly converts mouse and human fibroblasts to functional melanocytes. Induced melanocytes (iMels) activate melanocyte-specific networks, express components of pigment production and delivery system and produce melanosomes. Human iMels properly integrate into the dermal-epidermal junction and produce and deliver melanin pigment to surrounding keratinocytes in a 3D organotypic skin reconstruct. Human iMels generate pigmented epidermis and hair follicles in skin reconstitution assays in vivo. The generation of iMels has important implications for studies of melanocyte lineage commitment, pigmentation disorders and cell replacement therapies.
    Nature Communications 12/2014; 5:5807. DOI:10.1038/ncomms6807 · 10.74 Impact Factor
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    ABSTRACT: Over-expression of the HER2/neu receptor occurs in 20 to 30 percent of breast tumors and is linked to poorer prognosis. The HER2/neu expression status determines whether or not patient will receive trastuzumab-based treatment. In clinical practice, over-expression of HER2/neu is routinely identified using Immunohistochemistry (IHC) or Fluorescence in Situ Hybridization (FISH), both of which are invasive approaches requiring tissue samples. Serum assays for the Extra Cellular Domain of HER2/neu receptor (HER2 ECD) have been reported but the use is very limited due to serum interference factors (e.g. human anti-animal immunoglobulin antibodies) that lead to false test results and inconsistency with tissue Her2 status. We have developed an ELISA based approach using an MBB buffer to eliminate false results and to obtain more accurate assessment of HER2 ECD levels. Using this refined assay we retroactively measured HER2/neu levels from breast cancer patients and controls. Abnormal HER2 ECD levels were detected in about 32% of invasive breast cancer patients but not in controls or patients with benign diseases. In addition, we also showed that patients with elevated serum HER2 levels appeared to have worse survival regardless of treatments. In a small group of 12 Ductal Carcinoma in situ (DCIS) patients who received HER2/neu peptide vaccination and surgery, only one patient showed constantly rising HER2 levels after treatment and this patient had recurrence of HER2 positive tumor within 5 years. Our studies indicate that once the serum interference issue is resolved, serum HER2 ECD can have potential clinical utility to supplement the tissue based tests.
    11/2014; 4(3):151. DOI:10.4172/2155-9929.1000151
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    ABSTRACT: Macroautophagy, a catabolic process of cellular self-digestion, is an important tumor cell survival mechanism and a potential target in antineoplastic therapies. Recent discoveries have implicated autophagy in the cellular secretory process, but potential roles of autophagy-mediated secretion in modifying the tumor microenvironment are poorly understood. Furthermore, efforts to inhibit autophagy in clinical trials have been hampered by suboptimal methods to quantitatively measure tumor autophagy levels. Here, we leveraged the autophagy-based involvement in cellular secretion to identify shed proteins associated with autophagy levels in melanoma. The secretome of low-autophagy WM793 melanoma cells was compared to its highly autophagic metastatic derivative, 1205Lu in physiological 3-dimensional cell culture using quantitative proteomics. These comparisons identified candidate autophagy biomarkers IL1B (interleukin 1, beta), CXCL8 (chemokine (C-X-C motif) ligand 8), LIF (leukemia inhibitory factor), FAM3C (family with sequence similarity 3, member C), and DKK3 (dickkopf WNT signaling pathway inhibitor 3) with known roles in inflammation and tumorigenesis, and these proteins were subsequently shown to be elevated in supernatants of an independent panel of high-autophagy melanoma cell lines. Secretion levels of these proteins increased when low-autophagy melanoma cells were treated with the autophagy-inducing tat-BECN1 (Beclin 1) peptide and decreased when ATG7 (autophagy-related 7) was silenced in high-autophagy cells, thereby supporting a mechanistic link between these secreted proteins and autophagy. In addition, serum from metastatic melanoma patients with high tumor autophagy levels exhibited higher levels of these proteins than serum from patients with low-autophagy tumors. These results suggest that autophagy-related secretion affects the tumor microenvironment and measurement of autophagy-associated secreted proteins in plasma and possibly in tumors can serve as surrogates for intracellular autophagy dynamics in tumor cells.
    Autophagy 11/2014; 11(1). DOI:10.4161/15548627.2014.984273 · 11.42 Impact Factor
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    ABSTRACT: We have previously shown that Wnt5A drives invasion in melanoma. We have also shown that Wnt5A promotes resistance to therapy designed to target the BRAFV600E mutation in melanoma. Here, we show that melanomas characterized by high levels of Wnt5A respond to therapeutic stress by increasing p21 and expressing classical markers of senescence, including positivity for senescence-associated β-galactosidase (SA-β-gal), senescence associated heterochromatic foci (SAHF), H3K9Me chromatin marks, and PML bodies. We find that despite this, these cells retain their ability to migrate and invade. Further, despite the expression of classic markers of senescence like SA-β-gal and SAHF, these Wnt5A-high cells are able to colonize the lungs in in vivo tail-vein colony forming assays. This clearly underscores the fact that these markers do not indicate true senescence in these cells, but instead an adaptive stress response that allows the cells to evade therapy and invade. Notably, silencing Wnt5A reduces expression of these markers and decreases invasiveness. The combined data point to Wnt5A as a master regulator of an adaptive stress response in melanoma, which may contribute to therapy resistance.This article is protected by copyright. All rights reserved.
    Pigment Cell & Melanoma Research 11/2014; 28(2). DOI:10.1111/pcmr.12330 · 5.64 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):310-310. DOI:10.1158/1538-7445.AM2014-310 · 9.28 Impact Factor
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    ABSTRACT: Predicting clinical behavior of atypical Spitz tumors remains problematic. In this study, we assessed interobserver agreement of diagnosis by 13 expert dermatopathologists for atypical Spitz tumors (n=75). We determined which histomorphologic features were most heavily weighted for their diagnostic significance by the experts and also which histomorphologic features had a statistically significant correlation with clinical outcome. There was a low interobserver agreement among the experts in categorizing lesions as malignant versus nonmalignant (κ=0.30). The histomorphologic features that were given the most diagnostic significance by the experts were: consumption of the epidermis, atypical mitoses, high-grade cytologic atypia, and mitotic rate. Conversely, the histomorphologic features that most correlated with disease progression were: frequent mitoses, deep mitoses, asymmetry, high-grade cytologic atypia, and ulceration. The presence and/or pattern of pagetoid spread, consumption of the epidermis, and lymphoid aggregates demonstrated no association with clinical behavior. The results support the assertion that there is a lack of consensus in the assessment of atypical Spitz tumors by expert dermatopathologists. Importantly, many features used to distinguish conventional melanoma from nevi were not useful in predicting the behavior of atypical Spitz tumors. This study may provide some guidance regarding histologic assessment of these enigmatic tumors.
    The American journal of surgical pathology 03/2014; DOI:10.1097/PAS.0000000000000198 · 4.59 Impact Factor
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    ABSTRACT: Melanomas that result from mutations in the gene encoding BRAF often become resistant to BRAF inhibition (BRAFi), with multiple mechanisms contributing to resistance. While therapy-induced autophagy promotes resistance to a number of therapies, especially those that target PI3K/mTOR signaling, its role as an adaptive resistance mechanism to BRAFi is not well characterized. Using tumor biopsies from BRAFV600E melanoma patients treated either with BRAFi or with combined BRAF and MEK inhibition, we found that BRAFi-resistant tumors had increased levels of autophagy compared with baseline. Patients with higher levels of therapy-induced autophagy had drastically lower response rates to BRAFi and a shorter duration of progression-free survival. In BRAFV600E melanoma cell lines, BRAFi or BRAF/MEK inhibition induced cytoprotective autophagy, and autophagy inhibition enhanced BRAFi-induced cell death. Shortly after BRAF inhibitor treatment in melanoma cell lines, mutant BRAF bound the ER stress gatekeeper GRP78, which rapidly expanded the ER. Disassociation of GRP78 from the PKR-like ER-kinase (PERK) promoted a PERK-dependent ER stress response that subsequently activated cytoprotective autophagy. Combined BRAF and autophagy inhibition promoted tumor regression in BRAFi-resistant xenografts. These data identify a molecular pathway for drug resistance connecting BRAFi, the ER stress response, and autophagy and provide a rationale for combination approaches targeting this resistance pathway.
    The Journal of clinical investigation 02/2014; 124(3). DOI:10.1172/JCI70454 · 13.77 Impact Factor
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    ABSTRACT: Epithelial stem cells (EpSCs) in the hair follicle bulge are required for hair follicle growth and cycling. The isolation and propagation of human EpSCs for tissue engineering purposes remains a challenge. Here we develop a strategy to differentiate human iPSCs (hiPSCs) into CD200(+)/ITGA6(+) EpSCs that can reconstitute the epithelial components of the hair follicle and interfollicular epidermis. The hiPSC-derived CD200(+)/ITGA6(+) cells show a similar gene expression signature as EpSCs directly isolated from human hair follicles. Human iPSC-derived CD200(+)/ITGA6(+) cells are capable of generating all hair follicle lineages including the hair shaft, and the inner and outer root sheaths in skin reconstitution assays. The regenerated hair follicles possess a KRT15(+) stem cell population and produce hair shafts expressing hair-specific keratins. These results suggest an approach for generating large numbers of human EpSCs for tissue engineering and new treatments for hair loss, wound healing and other degenerative skin disorders.
    Nature Communications 01/2014; 5:3071. DOI:10.1038/ncomms4071 · 10.74 Impact Factor
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    ABSTRACT: Melanoma has a propensity for lymph node metastasis. However, the incidence of lymphatic invasion detected by histology alone in primary melanoma is disproportionately low in comparison to the incidence of positive sentinel lymph nodes (SLN). With the discovery of lymphatic endothelial cell markers, such as podoplanin and LYVE-1, lymphatic vessels can be reliably detected in formalin-fixed paraffin-embedded (FFPE) tissues. There is a now consensus that lymphatic invasion detected by immunohistochemical stains in primary melanoma is much more common than previously reported by histological examination alone. Immunohistochemical stains show that lymphangiogenesis and lymphatic invasion in primary melanoma may occur intratumorally or peritumorally, and lymphatic invasion is common across the range of tumor thicknesses in primary vertical growth phase (VGP) melanomas. A number of studies have shown that lymphatic invasion in primary melanoma is associated with a positive sentinel lymph node biopsy and a worse clinical outcome. Although not currently a part of the standard of care for staging of melanoma, the detection of lymphatic invasion in primary melanoma using immunohistochemical markers may be helpful in planning of therapy in some cases and may find a routine role in primary melanoma microscopic attributes in future.
    Methods in molecular biology (Clifton, N.J.) 01/2014; 1102:275-286. DOI:10.1007/978-1-62703-727-3_15 · 1.29 Impact Factor
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    ABSTRACT: Epithelial-mesenchymal transition (EMT) is an important developmental process hijacked by cancer cells for their dissemination. Here, we show that Exo70, a component of the exocyst complex, undergoes isoform switching mediated by ESRP1, a pre-mRNA splicing factor that regulates EMT. Expression of the epithelial isoform of Exo70 affects the levels of key EMT transcriptional regulators such as Snail and ZEB2 and is sufficient to drive the transition to epithelial phenotypes. Differential Exo70 isoform expression in human tumors correlates with cancer progression, and increased expression of the epithelial isoform of Exo70 inhibits tumor metastasis in mice. At the molecular level, the mesenchymal-but not the epithelial-isoform of Exo70 interacts with the Arp2/3 complex and stimulates actin polymerization for tumor invasion. Our findings provide a mechanism by which the exocyst function and actin dynamics are modulated for EMT and tumor invasion.
    Developmental Cell 12/2013; 27(5):560-573. DOI:10.1016/j.devcel.2013.10.020 · 10.37 Impact Factor
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    ABSTRACT: Melanoma microsatellitosis is classified as stage IIIB/C disease and is associated with a poor prognosis. Prognostic factors within this group, however, have not been well characterized. We performed a retrospective analysis of 1,621 patients undergoing sentinel lymph node (SLN) biopsy at our institution (1996-2011) to compare patients with (n = 98) and patients without (n = 1,523) microsatellites. Univariate and multivariate logistic and Cox regression analyses were used to identify factors associated with SLN positivity and melanoma-specific survival (MSS) in patients with microsatellites. Patients with microsatellites were older and had lesions with higher Clark level and greater thickness that more frequently had mitoses, ulceration, and lymphovascular invasion (LVI) (all p < 0.0001). In microsatellite patients, the SLN positivity rate was 43 %. Lesional ulceration (odds ratio [OR] = 2.9, 95 % confidence interval [CI] 1.5-8.6), absent tumor infiltrating lymphocytes (OR = 2.8, 95 % CI 1.1-7.1), and LVI (OR = 3.3, 95 % CI 1.7-10) were significantly associated with SLN positivity by multivariate analysis. With a median follow-up of 4.5 years in survivors, ulceration (hazards ratio [HR] = 3.4, 95 % CI 1.5-7.8) and >1 metastatic LN (HR = 2.7, 95 % CI 1.1-6.6) were significantly associated with decreased MSS by multivariate analysis. In patients without these prognostic factors, the 5-year MSS was 90 % (n = 49) compared with 50 % (n = 23) among patients with ulceration only, 51 % (n = 12) in those with >1 metastatic LN only, or 25 % in those with both (n = 14, p < 0.01). Microsatellitosis was frequently associated with multiple adverse pathologic features. In the absence of ulceration and >1 metastatic LN; however, the outcome for patients with microsatellites compared favorably to stage IIIB patients overall.
    Annals of Surgical Oncology 11/2013; DOI:10.1245/s10434-013-3388-5 · 3.94 Impact Factor
  • Society for Melanoma Research 2013 Congress Meeting, Philadelphia; 11/2013
  • Society for Melanoma Research 2013 Congress Meeting, Philadelphia; 11/2013
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    ABSTRACT: Tumor-associated macrophages (TAMs) play essential roles in tumor progression and metastasis. Tumor cells recruit myeloid progenitors and monocytes to the tumor site, where they differentiate into TAMs; however, this process is not well studied in humans. Here we show that human CD7, a T cell and NK cell receptor, is highly expressed by monocytes and macrophages. Expression of CD7 decreases in M-CSF differentiated macrophages and in Melanoma-conditioned Medium Induced Macrophages (MCMI/Mφ) in comparison to monocytes. A ligand for CD7, SECTM1 (Secreted and transmembrane protein 1), is highly expressed in many tumors, including melanoma cells. We show that SECTM1 binds to CD7 and significantly increases monocyte migration by activation of the PI3K pathway. In human melanoma tissues, tumor-infiltrating macrophages expressing CD7 are present. These melanomas, with CD7-positive inflammatory cell infiltrations, frequently highly express SECTM1, including an N-terminal, soluble form, which can be detected in the sera of metastatic melanoma patients but not in normal sera. Taken together, our data demonstrate that CD7 is present on monocytes and tumor macrophages, and that its ligand, SECTM1, is frequently expressed in corresponding melanoma tissues, possibly acting as a chemoattractant for monocytes to modulate the melanoma microenvironment.Journal of Investigative Dermatology accepted article preview online, 24 October 2013; doi:10.1038/jid.2013.437.
    Journal of Investigative Dermatology 10/2013; 134(4). DOI:10.1038/jid.2013.437 · 6.37 Impact Factor
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    ABSTRACT: The role for sentinel lymph node biopsy (SLNB) in patients with thin melanoma (≤1 mm) remains controversial. We examined a large cohort of patients with thin melanoma to better define predictors of SLN positivity. From 1995 to 2011, 781 patients with thin primary melanoma and evaluable clinicopathologic data underwent SLNB at our institution. Predictors of SLN positivity were determined using univariate and multivariate regression analyses, and patients were risk-stratified using a classification and regression tree (CART) analysis. In the study cohort (n = 781), 29 patients (3.7 %) had nodal metastases. In the univariate analysis, mitotic rate [odds ratio (OR) = 8.11, p = 0.005], Clark level (OR 4.04, p = 0.003), and thickness (OR 3.33, p = 0.011) were significantly associated with SLN positivity. In the multivariate analysis, MR (OR 7.01) and level IV-V (OR 3.45) remained significant predictors of SLN positivity. CART analysis initially stratified lesions by mitotic rate; nonmitogenic lesions (n = 273) had a 0.7 % SLN positivity rate versus 5.6 % in mitogenic lesions (n = 425). Mitogenic lesions were further stratified by Clark level; patients with level II-III had a 2.9 % SLN positivity rate (n = 205) versus 8.2 % with level IV-V (n = 220). With median follow-up of 6.3 years, five SLN-negative patients developed nodal recurrence and four SLN-positive patients died of disease. SLN positivity is low in patients with thin melanoma (3.7 %) and exceedingly so in nonmitogenic lesions (0.7 %). Appreciable rates of SLN positivity can be identified in patients with mitogenic lesions, particularly with concurrent level IV-V regardless of thickness. These factors may guide appropriate selection of patients with thin melanoma for SLNB.
    Annals of Surgical Oncology 10/2013; 21(2). DOI:10.1245/s10434-013-3313-y · 3.94 Impact Factor
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    ABSTRACT: Although BRAF and MEK inhibitors have proven clinical benefits in melanoma, most patients develop resistance. We report a de novo MEK2-Q60P mutation and BRAF gain in a melanoma from a patient who progressed on the MEK inhibitor trametinib and did not respond to the BRAF inhibitor dabrafenib. We also identified the same MEK2-Q60P mutation along with BRAF amplification in a xenograft tumor derived from a second melanoma patient resistant to the combination of dabrafenib and trametinib. Melanoma cells chronically exposed to trametinib acquired concurrent MEK2-Q60P mutation and BRAF-V600E amplification, which conferred resistance to MEK and BRAF inhibitors. The resistant cells had sustained MAPK activation and persistent phosphorylation of S6K. A triple combination of dabrafenib, trametinib, and the PI3K/mTOR inhibitor GSK2126458 led to sustained tumor growth inhibition. Hence, concurrent genetic events that sustain MAPK signaling can underlie resistance to both BRAF and MEK inhibitors, requiring novel therapeutic strategies to overcome it.
    Cell Reports 09/2013; 4(6). DOI:10.1016/j.celrep.2013.08.023 · 8.36 Impact Factor

Publication Stats

5k Citations
697.04 Total Impact Points

Institutions

  • 2005–2015
    • University of Pennsylvania
      • • Department of Pathology and Laboratory Medicine
      • • Department of Pathology
      Filadelfia, Pennsylvania, United States
  • 2000–2014
    • Hospital of the University of Pennsylvania
      • Department of Pathology and Laboratory Medicine
      Philadelphia, Pennsylvania, United States
  • 2006–2013
    • William Penn University
      Filadelfia, Pennsylvania, United States
  • 2005–2013
    • Wistar Institute
      • Melanoma Research Center
      Philadelphia, Pennsylvania, United States
  • 2012
    • University of Massachusetts Boston
      Boston, Massachusetts, United States
  • 2010
    • Yale University
      New Haven, Connecticut, United States
    • Fudan University
      • Cancer Hospital
      Shanghai, Shanghai Shi, China
  • 2009
    • Moffitt Cancer Center
      Tampa, Florida, United States