Synchronized Targeting of Notch and ERBB Signaling Suppresses Melanoma Tumor Growth through Inhibition of Notch1 and ERBB3.

Despite significant advances in melanoma therapy, melanoma remains the deadliest form of skin cancer, with a 5-year survival rate of only 15%. Thus, novel treatments are required to address this disease. Notch and ERBB are evolutionarily conserved signaling cascades required for the maintenance of melanocyte precursors. We show that active Notch1 (Notch1(NIC)) and active (phosphorylated) ERBB3 and ERBB2 correlate significantly and are similarly expressed in both mutated and wild-type BRAF melanomas, suggesting these receptors are co-reactivated in melanoma to promote survival. Whereas blocking either pathway triggers modest effects, combining a ?-secretase inhibitor to block Notch activation and a tyrosine kinase inhibitor to inhibit ERBB3/2 elicits synergistic effects, reducing cell viability by 90% and hampering melanoma tumor growth. Specific inhibition of Notch1 and ERBB3 mimics these results, suggesting these are the critical factors triggering melanoma tumor expansion. Notch and ERBB inhibition blunts AKT and NF?B signaling. Constitutive expression of NF?B partially rescues cell death. Blockade of both Notch and ERBB signaling inhibits the slow cycling JARID1B-positive cell population, which is critical for long-term maintenance of melanoma growth. We propose that blocking these pathways is an effective approach to treatment of melanoma patients regardless of whether they carry mutated or wild-type BRAF.

Impact of Socioeconomic Status and Ethnicity on Melanoma Presentation and Recurrence in Caucasian Patients.

OBJECTIVES: The impact of ethnicity and the socioeconomic status (SES) among Caucasians is not well studied. Here, we examine the impact of income on melanoma presentation and prognosis within a Caucasian cohort, accounting for ethnicity, as some reports suggest increased melanoma incidence in Ashkenazi Jewish (AJ) BRCA mutation carriers. METHODS: We studied prospectively enrolled primary melanoma patients at New York University. SES data were estimated using United States' Census Bureau data and patient zip codes. We evaluated associations between ethnicity, SES, and baseline characteristics using the χ² test and multivariate logistic regression. We compared survival distributions using Kaplan-Meier curves, log-rank tests, and Cox proportional hazard ratios. RESULTS: Of the 1,339 enrolled patients, AJ represented 32% (n = 423). Apart from AJ being older at presentation (p < 0.001), no significant differences were observed in baseline characteristics between ethnic groups. Patients with a median household income (MHI) lower than the median of the cohort were significantly more likely to present with advanced stages (p < 0.001) compared to patients with a higher MHI. Shorter overall (p = 0.016) and post-recurrence survival (p = 0.042) was also observed in patients from lower-income households. CONCLUSION: Data suggest that disparities in melanoma presentation in Caucasians stratify according to income independent of ethnic background.

FBXW7 modulates cellular stress response and metastatic potential through ​HSF1 post-translational modification.

​Heat-shock factor 1 (​HSF1) orchestrates the heat-shock response in eukaryotes. Although this pathway has evolved to help cells adapt in the presence of challenging conditions, it is co-opted in cancer to support malignancy. However, the mechanisms that regulate ​HSF1 and thus cellular stress response are poorly understood. Here we show that the ubiquitin ligase ​FBXW7α interacts with ​HSF1 through a conserved motif phosphorylated by ​GSK3ß and ​ERK1. ​FBXW7α ubiquitylates ​HSF1 and loss of ​FBXW7α results in impaired degradation of nuclear ​HSF1 and defective heat-shock response attenuation. ​FBXW7α is either mutated or transcriptionally downregulated in melanoma and ​HSF1 nuclear stabilization correlates with increased metastatic potential and disease progression. ​FBXW7α deficiency and subsequent ​HSF1 accumulation activates an invasion-supportive transcriptional program and enhances the metastatic potential of human melanoma cells. These findings identify a post-translational mechanism of regulation of the ​HSF1 transcriptional program both in the presence of exogenous stress and in cancer.