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| Status |
Public on Jun 30, 2013 |
| Title |
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 |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
|
| Summary |
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.
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| Overall design |
Total RNA obtained from melanooma cell lines treated for 24h with dabrafenib, trametinib or combination of dabrafenib and trametinib
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| Contributor(s) |
Rizos H, Pupo G |
| Citation(s) |
23645591 |
| Submission date |
Feb 28, 2013 |
| Last update date |
Aug 13, 2018 |
| Contact name |
Gulietta Pupo |
| E-mail(s) |
gulietta.pupo@sydney.edu.au
|
| Organization name |
University of Sydney
|
| Street address |
Darcy Road
|
| City |
Westmead |
| State/province |
NSW |
| ZIP/Postal code |
2145 |
| Country |
Australia |
| |
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| Platforms (1) |
| GPL10558 |
Illumina HumanHT-12 V4.0 expression beadchip |
|
| Samples (18)
|
| GSM1090085 |
SK-Mel28 BR6 Treated 100nM dabrafenib 24h |
| GSM1090086 |
SK-Mel28 BR8 Untreated |
| GSM1090087 |
SK-Mel28 BR8 Treated 100nM dabrafenib 24h |
| GSM1090088 |
SK-Mel28#8 CR401 Treated 100nM dabrafenib and 5nM trametinib 24h |
| GSM1090089 |
SK-Mel28#8 CR401 Untreated |
| GSM1090090 |
SK-Mel28#8 CR201 Treated 100nM dabrafenib and 5nM trametinib 24h |
| GSM1090091 |
SK-Mel28#8 CR201 Untreated |
| GSM1090092 |
SK-Mel28#8 Parent Treated 100nM dabrafenib and 5nM trametinib 24h |
| GSM1090093 |
SK-Mel28#8 Parent Untreated (Control for 100nM dabrafenib and 5nM trametinib 24h) |
| GSM1090094 |
SK-Mel28#8 MR201 Treated 10nM trametinib 24h |
| GSM1090095 |
SK-Mel28#8 MR201 Untreated |
| GSM1090096 |
SK-Mel28#8 MR105 Treated 10nM trametinib 24h |
| GSM1090097 |
SK-Mel28#8 MR105 Untreated |
| GSM1090098 |
SK-Mel28#8 Parent Treated 10nM trametinib 24h |
| GSM1090099 |
SK-Mel28#8 Parent Untreated (Control for 10nM trametinib 24h) |
|
| Relations |
| BioProject |
PRJNA191555 |
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