Long-term effects of BRAF inhibitors in melanoma treatment: friend or foe?

  title={Long-term effects of BRAF inhibitors in melanoma treatment: friend or foe?},
  author={Sarah Sloot and Inna V. Fedorenko and Keiran S. M. Smalley and Geoffrey Thomas Gibney},
  journal={Expert Opinion on Pharmacotherapy},
  pages={589 - 592}
The clinical development of selective BRAF inhibitors for metastatic BRAF V600 mutant melanoma patients has been a major breakthrough in targeted therapeutics. Objective response rates of approximately 50% have been observed in the Phase III studies of the BRAF inhibitors vemurafenib and dabrafenib. The side effects can be relatively common, including proliferative skin toxicities. The latter range from hyperkeratosis and keratoacanthomas (KAs) to squamous cell carcinomas (SCCs) and new primary… 
Response of BRAF inhibitor-associated squamous cell lung carcinoma to drug withdrawal.
Clinicians should be atuned to the risk of noncutaneous second malignancies induced by BRAFi, particularly in the setting of progression of an isolated lesion after prolonged therapy, particularly after withdrawal of BRAFi as the only change in therapy resulted in partial response maintained for more than 8 months.
BRAF inhibitor‐associated cutaneous squamous cell carcinoma: new mechanistic insight, emerging evidence for viral involvement and perspectives on clinical management
The emerging evidence pointing towards viral involvement in BRAF inhibitor‐induced cutaneous neoplasms and new perspectives on future therapeutic interventions are discussed, with a focus on factors that may contribute to disease pathogenesis.
The use of vemurafenib in Australian patients with unresectable or metastatic melanoma containing the V600 BRAF gene mutation
  • M. Brown, G. Long
  • Medicine, Biology
    Asia-Pacific journal of clinical oncology
  • 2014
An overview of the clinical development of vemurafenib, its attendant dose‐limiting toxicities and other AEs, recommendations for safety monitoring, supportive treatments of AEs and dose modifications, with the aim of maximizing the chances of continuing beneficial treatment are provided.
Dual BRAF/MEK blockade restores CNS responses in BRAF-mutant Erdheim–Chester disease patients following BRAF inhibitor monotherapy
Dual inhibition of BRAF and downstream MEK may be a safe and effective therapeutic strategy for BRAF-mutant ECD patients for whom BRAF inhibitor therapy proved insufficient and as such appropriate for the long-term management of CNS disease in ECD.
Optimizing the treatment of BRAF mutant melanoma
Two recent reports reveal new considerations for the optimal approach to targeting this key oncogenic pathway in melanoma, highlighting the importance of combination treatment and therapeutic scheduling.
Treatment of Langerhans cell histiocytosis: role of BRAF/MAPK inhibition.
  • O. Abla, S. Weitzman
  • Biology, Medicine
    Hematology. American Society of Hematology. Education Program
  • 2015
The recent discovery of somatic mutations in ARAF and in MAP2K1, which lead to activation of the RAS-RAF-MEK -ERK pathway in the setting of wild-type BRAF, as well as the finding that activating mutation in MAP1 are relatively insensitive to MEK inhibitors, suggest that a more detailed understanding of this pathway in LCH may be necessary for the development of more effective targeted therapies.
Concurrent MEK targeted therapy prevents MAPK pathway reactivation during BRAFV600E targeted inhibition in a novel syngeneic murine glioma model
Combined BRAFV600E and MEK inhibitor treatment was more effective in reducing tumor growth and extending animal subject survival, as corresponding to sustained MAPK pathway inhibition.
MAPK Pathway‐Targeted Therapies
  • K. Rubin
  • Medicine
    Clinical journal of oncology nursing
  • 2017
An overview of the key toxicities and associated management strategies of the characteristic adverse event (AE) profile associated with agents targeting the MAPK pathway is provided to provide nurses with an overview of how to optimize treatment outcomes.
A patent review of BRAF inhibitors: 2013-2018
This review gives an overview of recently approved BRAF agents on function mode, therapeutic efficacy, and deficiency, based on which current challenges and corresponding strategies were presented.


Paradoxical oncogenesis—the long-term effects of BRAF inhibition in melanoma
The concept of pre-existing populations of partly transformed cells with malignant potential that might be present in various organ systems, and the rationale for novel therapeutic strategies for the management of BRAF-inhibitor-induced neoplasia are discussed.
Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations.
Dabrafenib and trametinib were safely combined at full monotherapy doses, and the rate of pyrexia was increased with combination therapy, whereas the rates of proliferative skin lesions was nonsignificantly reduced.
Antitumor activity of the selective pan-RAF inhibitor TAK-632 in BRAF inhibitor-resistant melanoma.
It is demonstrated that the selective pan-RAF inhibitor TAK-632 suppresses RAF activity in BRAF wild-type cells with minimal RAF paradoxical activation and demonstrates potent antiproliferative effects both on NRAS-mutated melanoma cells and BRAF-mutation melanomas cells with acquired resistance to BRAF inhibitors through NRAS mutation or BRAF truncation.
Cutaneous Adverse Events to Type I BRAF Inhibitors: An Analysis of Effects Associated with Each Inhibitor and Therapeutic Time Interval to Onset
This comprehensive literature review provides an all-inclusive list of cutaneous adverse effects associated with selective class I RAF inhibitors, specific adverse effectsassociated with each inhibitor, and the therapeutic time interval associated with the onset of all reported lesion types.
Improved survival with MEK Inhibition in BRAF-mutated melanoma for the METRIC Study Group
Tametinib, as compared with chemotherapy, improved rates of progression-free and overall survival among patients who had metastatic melanoma with a BRAF V600E or V600K mutation.
Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors.
SCH772984 is a novel and selective inhibitor of ERK1/2 that displays behaviors of both type I and type II kinase inhibitors and effectively inhibited MAPK signaling and cell proliferation in BRAF or MEK inhibitor-resistant models as well as in tumor cells resistant to concurrent treatment with BRAF and MEK inhibitors.
RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors.
BACKGROUND Cutaneous squamous-cell carcinomas and keratoacanthomas are common findings in patients treated with BRAF inhibitors. METHODS We performed a molecular analysis to identify oncogenic
Cutaneous toxicities of RAF inhibitors.
Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma.
  • G. Long, A. Menzies, R. Kefford
  • Medicine, Biology
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology
  • 2011
The presence of mutant BRAF had no impact on the disease-free interval from diagnosis of first-ever melanoma to first distant metastasis; however, it may have impacted survival thereafter.