BRAF inhibitors in metastatic non-small cell lung cancer

Anguera, Geòrgia; Majem, Margarita

doi:10.21037/jtd.2018.01.129

Cited by 25 publications

(16 citation statements)

References 21 publications

(20 reference statements)

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“…KRAS mutations are common in lung adenoma, pancreatic ductal cancer and colorectal cancer whilst NRAS mutations are found in melanoma [ 9 ]. BRAF mutations occur in almost all (>97%) hairy cell leukaemia [ 11 ], ∼50% of melanoma [ 12 ] and conventional papillary thyroid cancers [ 13 ], and up to 7% of lung adenomas [ 14 ]. MEK mutations are very rare and can be either RAF-independent, RAF-regulated or RAF-dependent [ 15 ].…”

Section: Introduction To the Ras–raf–mek1/2–erk1/2 Pathwaymentioning

confidence: 99%

Inhibition of RAF dimers: it takes two to tango

Cook

2020

Biochemical Society Transactions

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The RAS-regulated RAF–MEK1/2–ERK1/2 pathway promotes cell proliferation and survival and RAS and BRAF proteins are commonly mutated in cancer. This has fuelled the development of small molecule kinase inhibitors including ATP-competitive RAF inhibitors. Type I and type I½ ATP-competitive RAF inhibitors are effective in BRAFV600E/K-mutant cancer cells. However, in RAS-mutant cells these compounds instead promote RAS-dependent dimerisation and paradoxical activation of wild-type RAF proteins. RAF dimerisation is mediated by two key regions within each RAF protein; the RKTR motif of the αC-helix and the NtA-region of the dimer partner. Dimer formation requires the adoption of a closed, active kinase conformation which can be induced by RAS-dependent activation of RAF or by the binding of type I and I½ RAF inhibitors. Binding of type I or I½ RAF inhibitors to one dimer partner reduces the binding affinity of the other, thereby leaving a single dimer partner uninhibited and able to activate MEK. To overcome this paradox two classes of drug are currently under development; type II pan-RAF inhibitors that induce RAF dimer formation but bind both dimer partners thus allowing effective inhibition of both wild-type RAF dimer partners and monomeric active class I mutant RAF, and the recently developed “paradox breakers” which interrupt BRAF dimerisation through disruption of the αC-helix. Here we review the regulation of RAF proteins, including RAF dimers, and the progress towards effective targeting of the wild-type RAF proteins

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Section: Introduction To the Ras–raf–mek1/2–erk1/2 Pathwaymentioning

confidence: 99%

Inhibition of RAF dimers: it takes two to tango

Cook

2020

Biochemical Society Transactions

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“…Although data about the effect of BRAF mutation on outcomes, including disease progression, in advanced melanoma are limited (Bhatia et al, 2015), patients with BRAF-V600 mutation have a lower overall survival (OS) and are at higher risk of death than those without the mutation (BRAF wild type); therefore, a different approach is recommended for individuals with advanced melanoma and BRAF-V600 mutation (Ekedahl et al, 2013;Long et al, 2011;Safaee Ardekani, Jafarnejad, Tan, Saeedi, & Li, 2012). Moreover, the importance of targeted therapies in other types of neoplasm, such as metastatic non-small cell lung cancer, has been described as patients with BRAF-V600E mutation have poor prognosis and low response to platinum chemotherapy, which lead to the use of targeted therapies (Anguera & Majem, 2018).…”

mentioning

confidence: 99%

Efficacy and safety of dabrafenib–trametinib in the treatment of unresectable advanced/metastatic melanoma with BRAF‐V600 mutation: A systematic review and network meta‐analysis

Garzón‐Orjuela

Prieto-Pinto

Lasalvia

et al. 2019

Dermatologic Therapy

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The current systematic review aimed to evaluate and compare the efficacy and safety of dabrafenib–trametinib with those of other therapeutic alternatives in the treatment of patients with unresectable advanced/metastatic melanoma with BRAF‐V600 mutation. The search was carried out on four databases up to July 2018. Two separate network meta‐analyses (NMA) were performed using the frequentist method (random effects): one with an exclusive population with BRAF‐V600 mutation (NMA‐pBRAFV600) and another with mixed population (with or without the mutation: NMA‐pMixed). An evidence profile was included using the GRADE method for NMA. The validity of the final estimator in the NMA‐pMixed was assessed via a sensitivity analysis. Nine clinical trials were included in the NMA‐pBRAFV600. Dabrafenib–trametinib was found to have a favorable effect on overall survival (OS) and progression‐free survival (PFS) compared with dabrafenib, vemurafenib, and dacarbazine and on partial response rate (PRR) and overall response rate compared with dacarbazine and vemurafenib. In the NMA‐pMixed, dabrafenib–trametinib was found to have a positive effect on OS versus ipilimumab 3 mg/kg and on PFS and PRR versus ipilimumab, nivolumab, and pembrolizumab. However, dabrafenib–trametinib and vemurafenib–cobimetinib significantly differed in terms of efficacy. In addition, dabrafenib–trametinib has a favorable effect on Grades 3 and 4 adverse events.

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“…Lung malignancy is one of the most common malignancies, with a high rate of mortality [2–4]. The more common locations tend to be hilar nodal involvement, liver, adrenals, bone and brain.…”

Section: Discussionmentioning

confidence: 99%

“…Cutaneous metastases are rare sites of metastasis, with an incidence of 5.3% [1]. Whilst the most common internal malignancy overall remains breast cancer, 1–12% of patients with lung cancer may develop cutaneous metastases [2, 3]. The presence of a firm, rapidly growing papular or nodular lesion should prompt the clinician to maintain suspicion of internal malignancy.…”

Section: Introductionmentioning

confidence: 99%

Cutaneous metastases as a presenting sign of metastatic NSCLC

McSweeney¹,

Tan²

2019

Journal of Surgical Case Reports

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Cutaneous metastases are rare and often late signs of an internal malignancy; however, this can be the presenting sign in very rare cases. These typically have a characteristic appearance and distribution based on the underlying malignancy but can be difficult to distinguish from other malignant or benign dermatoses. We report a case of a 69-year-old female who presented for elective excision of two cutaneous, fast-growing lesions on the chest wall. The patient’s past medical history is significant for a 45-pack-year smoking history. Pre-operative chest radiograph revealed a right upper lobe mass, with the lesions ultimately representing cutaneous metastases of a non-small-cell lung cancer. Although cutaneous metastases have been reported, difficulty remains in distinguishing other causes of cutaneous lesions from cutaneous metastases in the predominantly asymptomatic patient.

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BRAF inhibitors in metastatic non-small cell lung cancer

Cited by 25 publications

References 21 publications

Inhibition of RAF dimers: it takes two to tango

Inhibition of RAF dimers: it takes two to tango

Efficacy and safety of dabrafenib–trametinib in the treatment of unresectable advanced/metastatic melanoma with BRAF‐V600 mutation: A systematic review and network meta‐analysis

Cutaneous metastases as a presenting sign of metastatic NSCLC

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