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Anti-proliferative effects of continued mitogen activated protein kinase pathway inhibition following acquired resistance to BRAF and/or MEK inhibition in melanoma: Implications for treatment beyond disease progression

ABSTRACT: Inhibitors of the MAPKs, BRAF and MEK, induce tumor regression in the majority of patients with BRAF-mutant metastatic melanoma. The clinical benefit of MAPK inhibitors is restricted by the development of acquired resistance with half of those who benefit having progressed by 6-7 months and long-term responders uncommon. There remains no agreed treatment strategy on disease progression in these patients. Without published evidence, fears of accelerated disease progression on inhibitor withdrawal have led to the continuation of drugs beyond formal disease progression. We now demonstrate that treatment with MAPK inhibitors beyond disease progression can provide significant clinical benefit, and the withdrawal of these inhibitors led to a marked increase in the rate of disease progression in two patients. We also show that MAPK inhibitors retain partial activity in acquired resistant melanoma by examining drug-resistant clones generated to dabrafenib, trametinib or the combination of these drugs. All resistant sublines displayed a markedly slower rate of proliferation when exposed to MAPK inhibitors, and this coincided with a reduction in MAPK signalling, decrease in BrdU incorporation and S-phase inhibition. This cytostatic effect was also associated diminished levels of cyclin D1 and p-pRb.. Two short-term melanoma cultures generated from resistant tumour biopsies also responded to MAPK inhibition with comparable inhibitory changes in proliferation and MAPK signalling. These data provide a rationale for the continuation of BRAF and MEK inhibitors after disease progression and support the development of clinical trials to examine this strategy. Total RNA obtained from melanooma cell lines treated for 24h with dabrafenib, trametinib or combination of dabrafenib and trametinib

ORGANISM(S): Homo sapiens

SUBMITTER: Pupo Gulietta

PROVIDER: S-ECPF-GEOD-44753 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:Resistance to therapy with BRAF kinase inhibitors is associated with reactivation of the mitogen-activated protein kinase (MAPK) pathway. To address this problem, we conducted a phase 1 and 2 trial of combined treatment with dabrafenib, a selective BRAF inhibitor, and trametinib, a selective MAPK kinase (MEK) inhibitor.In this open-label study involving 247 patients with metastatic melanoma and BRAF V600 mutations, we evaluated the pharmacokinetic activity and safety of oral dabrafenib (75 or 150 mg twice daily) and trametinib (1, 1.5, or 2 mg daily) in 85 patients and then randomly assigned 162 patients to receive combination therapy with dabrafenib (150 mg) plus trametinib (1 or 2 mg) or dabrafenib monotherapy. The primary end points were the incidence of cutaneous squamous-cell carcinoma, survival free of melanoma progression, and response. Secondary end points were overall survival and pharmacokinetic activity.Dose-limiting toxic effects were infrequently observed in patients receiving combination therapy with 150 mg of dabrafenib and 2 mg of trametinib (combination 150/2). Cutaneous squamous-cell carcinoma was seen in 7% of patients receiving combination 150/2 and in 19% receiving monotherapy (P=0.09), whereas pyrexia was more common in the combination 150/2 group than in the monotherapy group (71% vs. 26%). Median progression-free survival in the combination 150/2 group was 9.4 months, as compared with 5.8 months in the monotherapy group (hazard ratio for progression or death, 0.39; 95% confidence interval, 0.25 to 0.62; P<0.001). The rate of complete or partial response with combination 150/2 therapy was 76%, as compared with 54% with monotherapy (P=0.03).Dabrafenib and trametinib were safely combined at full monotherapy doses. The rate of pyrexia was increased with combination therapy, whereas the rate of proliferative skin lesions was nonsignificantly reduced. Progression-free survival was significantly improved. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01072175.).

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Anti-proliferative effects of continued mitogen activated protein kinase pathway inhibition following acquired resistance to BRAF and/or MEK inhibition in melanoma: Implications for treatment beyond disease progression

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