Targeted therapies with MAPK inhibitors (MAPKi) are faced with severe problems of resistance in BRAF‐mutant melanoma.,In parallel to the acquisition of genetic mutations, melanoma cells may also adapt to the drugs through phenotype switching.,The ZEB1 transcription factor, a known inducer of EMT and invasiveness, is now considered as a genuine oncogenic factor required for tumor initiation, cancer cell plasticity, and drug resistance in carcinomas.,Here, we show that high levels of ZEB1 expression are associated with inherent resistance to MAPKi in BRAFV 600‐mutated cell lines and tumors.,ZEB1 levels are also elevated in melanoma cells with acquired resistance and in biopsies from patients relapsing while under treatment.,ZEB1 overexpression is sufficient to drive the emergence of resistance to MAPKi by promoting a reversible transition toward a MITF low/p75high stem‐like and tumorigenic phenotype.,ZEB1 inhibition promotes cell differentiation, prevents tumorigenic growth in vivo, sensitizes naive melanoma cells to MAPKi, and induces cell death in resistant cells.,Overall, our results demonstrate that ZEB1 is a major driver of melanoma cell plasticity, driving drug adaptation and phenotypic resistance to MAPKi.
Ipilimumab is a monoclonal antibody that antagonizes cytotoxic T lymphocyte antigen-4, a negative regulator of the immune system.,The authors report on advanced refractory melanoma patients treated in a compassionate use trial of ipilimumab at the Memorial Sloan-Kettering Cancer Center.,Patients with advanced refractory melanoma were treated in a compassionate use trial with ipilimumab 10 mg/kg every 3 weeks for 4 doses.,Those with evidence of clinical benefit at Week 24 (complete response [CR], partial response [PR], or stable disease [SD]) then received ipilimumab every 12 weeks.,A total of 53 patients were enrolled, with 51 evaluable.,Grade 3/4 immune-related adverse events were noted in 29% of patients, with the most common immune-related adverse events being pruritus (43%), rash (37%), and diarrhea (33%).,On the basis of immune-related response criteria, the response rate (CR + PR) was 12% (95% confidence interval [CI], 5%-25%), whereas 29% had SD (95% CI, 18%-44%).,The median progression-free survival was 2.6 months (95% CI, 2.3-5.2 months), whereas the median overall survival (OS) was 7.2 months (95% CI, 4.0-13.3 months).,Patients with an absolute lymphocyte count (ALC) ≥1000/μL after 2 ipilimumab treatments (Week 7) had a significantly improved clinical benefit rate (51% vs 0%; P = .01) and median OS (11.9 vs 1.4 months; P < .001) compared with those with an ALC <1000/μL.,The results confirm that ipilimumab is clinically active in patients with advanced refractory melanoma.,The ALC after 2 ipilimumab treatments appears to correlate with clinical benefit and OS, and should be prospectively validated.,Cancer 2010.,© 2010 American Cancer Society.,This description of 51 patients with advanced, treatment-refractory melanoma who were enrolled in a compassionate use trial of ipilimumab at Memorial Sloan-Kettering Cancer Center confirms that ipilimumab is active in this disease setting.,In addition, the results suggest that the absolute lymphocyte count after 2 ipilimumab treatments (at Week 7) highly correlates with the rate of clinical benefit at Week 24 and overall survival.