ABSTRACT
Vemurafenib and dabrafenib selectively inhibit the v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) kinase, resulting in high response rates and increased survival in melanoma. Approximately 22% of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma (cSCC) during therapy. The prevailing explanation for this is drug-induced paradoxical ERK activation, resulting in hyperproliferation. Here we show an unexpected and novel effect of vemurafenib/PLX4720 in suppressing apoptosis through the inhibition of multiple off-target kinases upstream of c-Jun N-terminal kinase (JNK), principally ZAK. JNK signaling is suppressed in multiple contexts, including in cSCC of vemurafenib-treated patients, as well as in mice. Expression of a mutant ZAK that cannot be inhibited reverses the suppression of JNK activation and apoptosis. Our results implicate suppression of JNK-dependent apoptosis as a significant, independent mechanism that cooperates with paradoxical ERK activation to induce cSCC, suggesting broad implications for understanding toxicities associated with BRAF inhibitors and for their use in combination therapies. DOI: http://dx.doi.org/10.7554/eLife.00969.001.
Subject(s)
Apoptosis/drug effects , Imidazoles/pharmacology , Indoles/pharmacology , MAP Kinase Kinase 4/antagonists & inhibitors , Oximes/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Signal Transduction/drug effects , Sulfonamides/pharmacology , Animals , Humans , MAP Kinase Kinase 4/metabolism , Mice , Mice, Hairless , VemurafenibABSTRACT
BACKGROUND: The UBE4B gene, which is located on chromosome 1p36, encodes a ubiquitin ligase that interacts with hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs), a protein involved in epidermal growth factor receptor (EGFR) trafficking, suggesting a link between EGFR trafficking and neuroblastoma pathogenesis. The authors analyzed the roles of UBE4B in the outcomes of patients with neuroblastoma and in neuroblastoma tumor cell proliferation, EGFR trafficking, and response to EGFR inhibition. METHODS: The association between UBE4B expression and the survival of patients with neuroblastoma was examined using available microarray data sets. UBE4B and EGFR protein levels were measured in patient tumor samples, EGFR degradation rates were measured in neuroblastoma cell lines, and the effects of UBE4B on neuroblastoma tumor cell growth were analyzed. The effects of the EGFR inhibitor cetuximab were examined in neuroblastoma cells that expressed wild-type and mutant UBE4B. RESULTS: Low UBE4B gene expression is associated with poor outcomes in patients with neuroblastoma. UBE4B overexpression reduced neuroblastoma tumor cell proliferation, and UBE4B expression was inversely related to EGFR expression in tumor samples. EGFR degradation rates correlated with cellular UBE4B levels. Enhanced expression of catalytically active UBE4B resulted in reduced sensitivity to EGFR inhibition. CONCLUSIONS: The current study demonstrates associations between UBE4B expression and the outcomes of patients with neuroblastoma and between UBE4B and EGFR expression in neuroblastoma tumor samples. Moreover, levels of UBE4B influence neuroblastoma tumor cell proliferation, EGFR degradation, and response to EGFR inhibition. These results suggest UBE4B-mediated growth factor receptor trafficking may contribute to the poor prognosis of patients who have neuroblastoma tumors with 1p36 deletions and that UBE4B expression may be a marker that can predict responses of neuroblastoma tumors to treatment.
Subject(s)
ErbB Receptors/antagonists & inhibitors , Neuroblastoma/drug therapy , Neuroblastoma/metabolism , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism , Ubiquitin-Protein Ligase Complexes/genetics , Ubiquitin-Protein Ligase Complexes/metabolism , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal, Humanized , Cell Line, Tumor , Cell Proliferation/drug effects , Cetuximab , Chromosome Deletion , Chromosomes, Human, Pair 1 , ErbB Receptors/metabolism , Humans , Neuroblastoma/genetics , Neuroblastoma/mortality , Neuroblastoma/pathology , Treatment Outcome , Ubiquitin-Protein LigasesSubject(s)
Antineoplastic Agents, Phytogenic/adverse effects , Hand-Foot Syndrome/etiology , Paclitaxel/adverse effects , Aged , Antineoplastic Agents, Phytogenic/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/drug therapy , Carcinoma, Ductal, Breast/pathology , Female , Hand-Foot Syndrome/pathology , Humans , Paclitaxel/therapeutic useABSTRACT
Female pattern hair loss (FPHL) was originally described as synonymous with androgenetic alopecia. However, the role of androgens in FPHL has not been proven, and the etiology is not yet defined. Several patterns of hair loss in women have been described, in addition to descriptions of scarring alopecias mimicking FPHL. In this paper, we discuss FPHL as an entity other than androgenetic alopecia and suggest that de-emphasizing the physicians reliance on pattern in the diagnosis of hair loss in women, and instead utilizing other tools including dermoscopy and histopathology, would benefit clinician's efforts in treating alopecias.
Subject(s)
Alopecia/etiology , Alopecia/pathology , Alopecia/diagnosis , Alopecia/physiopathology , Androgens/physiology , Dermoscopy , Estrogens/physiology , Female , Humans , Iron Deficiencies , Prolactin/physiologyABSTRACT
A 24-month follow up of a previously reported case of successful hyaluronic acid filler use in steroid atrophy is presented. The patient had persistence of the volume and appearance of her scar with sustained satisfaction 24 months after hyaluronic acid treatment, without the need for repeat injection. This case suggests expansion of the use of hyaluronic acid fillers to include scar atrophy, as persistence of a desired cosmetic appearance for 2 years is demonstrated.
Subject(s)
Cicatrix/drug therapy , Cicatrix/pathology , Atrophy/drug therapy , Female , Follow-Up Studies , Humans , Hyaluronic Acid/pharmacokinetics , Hyaluronic Acid/therapeutic use , Middle AgedABSTRACT
BACKGROUND: ERBB receptor tyrosine kinases can mediate proliferation, migration, adhesion, differentiation, and survival in many types of cells and play critical roles in many malignancies. Recent reports suggest a role for EGFR signaling in proliferation and survival of neuroblastoma, a common form of pediatric cancer that often has an extremely poor outcome. METHODS: The authors examined ERBB family expression in neuroblastoma cell lines and patient samples by flow cytometry, western blot, and quantitative real time polymerase chain reaction (Q-PCR). Response to ERBB inhibition was assessed in vitro by cell-cycle analysis and western blot and in vivo by serial tumor-size measurements. RESULTS: A panel of neuroblastoma cell lines and primary patient tumors expressed EGFR, HER-3, and HER-4, with HER-2 in some tumors. HER-4 mRNA was expressed predominantly in cleavable isoforms. Whereas EGFR inhibition with erlotinib and pan-ERBB inhibition with CI-1033 inhibited EGF-induced phosphorylation of EGFR, AKT, and ERK1/2, only CI-1033 induced growth inhibition and dose-dependent apoptosis in vitro. Both CI-1033 and erlotinib treatment of neuroblastoma xenograft tumors resulted in decreased tumor growth in vivo, although CI-1033 was more effective. In vivo expression of EGFR was observed predominantly in vascular endothelial cells. CONCLUSIONS: Pan-ERBB inhibition is required for ERBB-related neuroblastoma apoptosis in vitro, although EGFR contributes indirectly to tumor growth in vivo. Inhibition of EGFR in endothelial cells may be an important aspect of erlotinib's impact on neuroblastoma growth in vivo. Our results suggest that non-EGFR ERBB family members contribute directly to neuroblastoma growth and survival, and pan-ERBB inhibition represents a potential therapeutic target for treating neuroblastoma.