Antiproliferative effects of continued mitogen-activated protein kinase pathway inhibition following acquired resistance to BRAF and/or MEK inhibition in melanoma

Inhibitors of the mitogen-activated protein kinases (MAPK), BRAF, and MAP-ERK kinase (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...

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Bibliographic Details
Published in:Molecular cancer therapeutics 2013-07, Vol.12 (7), p.1332-1342
Main Authors: Carlino, Matteo S, Gowrishankar, Kavitha, Saunders, Catherine A B, Pupo, Gulietta M, Snoyman, Stephanie, Zhang, Xu Dong, Saw, Robyn, Becker, Therese M, Kefford, Richard F, Long, Georgina V, Rizos, Helen
Format: Article
Language:English
Subjects:
Apoptosis - drug effects
Cell Line, Tumor
Drug Resistance, Neoplasm
Gene Expression
Humans
Imidazoles - adverse effects
Imidazoles - therapeutic use
Male
Melanoma - drug therapy
Melanoma - pathology
Middle Aged
Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors
Mitogen-Activated Protein Kinase Kinases - metabolism
Oximes - adverse effects
Oximes - therapeutic use
Proto-Oncogene Proteins B-raf - antagonists & inhibitors
Proto-Oncogene Proteins B-raf - metabolism
Pyridones - adverse effects
Pyridones - therapeutic use
Pyrimidinones - adverse effects
Pyrimidinones - therapeutic use
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Summary:Inhibitors of the mitogen-activated protein kinases (MAPK), BRAF, and MAP-ERK kinase (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 to 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 show 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 signaling, decrease in bromodeoxyuridine incorporation, and S-phase inhibition. This cytostatic effect was also associated with diminished levels of cyclin D1 and p-pRb. Two short-term melanoma cultures generated from resistant tumor biopsies also responded to MAPK inhibition, with comparable inhibitory changes in proliferation and MAPK signaling. 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.
ISSN:1535-7163
1538-8514
DOI:10.1158/1535-7163.MCT-13-0011