Bench to bedside: mechanistic principles of targeting the RAF kinase in melanoma

Abstract

Melanoma, in its advanced form, is an aggressive cancer with a poor prognosis. To date, no therapeutic modality has afforded a high likelihood of curative outcome, with the exception of early surgical resection in patients diagnosed with local disease. However, recent advances in our understanding of the molecular mechanisms and pathophysiology of melanoma have paved the way towards the development of targeted therapeutics. A central player in melanomagenesis is the RAF family of kinases. Key mechanistic details regarding the regulation of RAF kinases have now begun to emerge. Already, vemurafenib, a tailored kinase inhibitor of aberrant RAF function in melanoma, has led to clinical benefit. Despite vemurafenib's success, acquired resistance to the drug warrants the need for further drug development. In this review, we discuss the critical role of RAF dimerization in both melanomagenesis and resistance to RAF inhibitors such as vemurafenib. We also highlight the potential for inhibitors of RAF dimerization to lead to improved outcomes in patients with advanced melanoma.

Nanotechnology Addressing Cutaneous Melanoma: The Italian Landscape

“…Dabrafenib is another highly potent BRAFi, 100 times more selective for mutated BRAFV600E compared to wild type [74]. The main limitation of BRAFi is the quick development of resistance [75,76] due to MAPK pathway reactivation [77][78][79]. Therefore, in order to counteract resistance mechanisms, MEKi have been employed, including trametinib, which was approved by the FDA in 2013 for the treatment of metastatic melanoma with BRAFV600E mutations [75].…”

“…The main limitation of BRAFi is the quick development of resistance [75,76] due to MAPK pathway reactivation [77][78][79]. Therefore, in order to counteract resistance mechanisms, MEKi have been employed, including trametinib, which was approved by the FDA in 2013 for the treatment of metastatic melanoma with BRAFV600E mutations [75]. Therefore, BRAFi and MEKi combinations have become the standard-of-care treatment for unresectable or distant metastatic V600Emutant melanoma.…”

Spotlight on pembrolizumab in the treatment of advanced melanoma

“… 5 Furthermore, only ~50%–70% of patients with specific mutations in the BRAF gene of the MAP kinase cascade can benefit from these inhibitors with a median duration of response of 5–7 months on BRAF inhibitor monotherapy. 6 Combination therapy with multiple inhibitors targeting BRAF and MEK in the MAP kinase cascade improves response rates and progression-free survival, but this tactic is also prone to the development of resistance with prolonged treatment. 7 As such, tremendous efforts are ongoing toward developing novel approaches for the effective treatment of advanced melanomas.…”