Mitochondrial dysfunction and immune suppression in BRAF V600E-mutated metastatic melanoma.
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ABSTRACT:
SUBMITTER: Pinto de Almeida N
PROVIDER: S-EPMC11259597 | biostudies-literature | 2024 Jul
REPOSITORIES: biostudies-literature
Publications
Mitochondrial dysfunction and immune suppression in BRAF V600E-mutated metastatic melanoma.
Pinto de Almeida Natália N Jánosi Ágnes Judit ÁJ Hong Runyu R Rajeh Ahmad A Nogueira Fábio F Szadai Leticia L Szeitz Beata B Pla Parada Indira I Doma Viktória V Woldmar Nicole N Guedes Jéssica J Újfaludi Zsuzsanna Z Bartha Aron A Kim Yonghyo Y Welinder Charlotte C Baldetorp Bo B Kemény Lajos Vince LV Pahi Zoltan Z Wan Guihong G Nguyen Nga N Pankotai Tibor T Győrffy Balázs B Pawłowski Krzysztof K Horvatovich Peter P Szasz Attila Marcell AM Sanchez Aniel A Kuras Magdalena M Rodriguez Murillo Jimmy J Betancourt Lazaro L Domont Gilberto B GB Semenov Yevgeniy R YR Yu Kun-Hsing KH Kwon Ho Jeong HJ Németh István Balázs IB Fenyő David D Wieslander Elisabet E Marko-Varga György G Gil Jeovanis J
Clinical and translational medicine 20240701 7
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Project description:To examine the association between level and patterns of baseline intra-tumoural BRAF(V600E) protein expression and clinical outcome of BRAF(V600E) melanoma patients treated with selective BRAF inhibitors.Fifty-eight BRAF(V600E) metastatic melanoma patients treated with dabrafenib or vemurafenib on clinical trials had pre-treatment tumour BRAF(V600E) protein expression immunohistochemically (IHC) assessed using the BRAF V600E mutant-specific antibody VE1. Sections were examined for staining intensity (score 1-3) and percentage of immunoreactive tumour cells, and from this an immunoreactive score (IRS) was derived (intensity × per cent positive/10). The presence of intra-tumoural heterogeneity for BRAF(V600E) protein expression was also assessed. BRAF(V600E) expression was correlated with RECIST response, time to best response (TTBR), progression-free survival (PFS) and overall survival (OS).Expression was generally high (median IRS 28 (range 5-30)) and homogeneous (78%). Expression of mutated protein BRAF(V600E) as measured by intensity, per cent immunoreactive cells, or IRS did not correlate with RECIST response, TTBR, PFS or OS, including on multivariate analysis. Heterogeneity of staining was seen in 22% of cases and did not correlate with outcome.In the current study population, IHC-measured pre-treatment BRAF(V600E) protein expression does not predict response or outcome to BRAF inhibitor therapy in BRAF(V600E) metastatic melanoma patients.
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Project description:BackgroundMost mutations in melanoma affect one critical amino acid on BRAF gene, resulting in the V600E substitution. Patient management is often based on the use of specific inhibitors targeting this mutation.MethodsDNA and RNA mutation status was assessed in 15 melanoma cell lines by Sanger sequencing and RNA-seq. We tested the cell lines responsiveness to BRAF inhibitors (vemurafenib and PLX4720, BRAF-specific and sorafenib, BRAF non-specific). Cell proliferation was assessed by MTT colorimetric assay. BRAF V600E RNA expression was assessed by qPCR. Expression level of phosphorylated-ERK protein was assessed by Western Blotting as marker of BRAF activation.ResultsThree cell lines were discordant in the mutation detection (BRAF V600E at DNA level/Sanger sequencing and BRAF WT on RNA-seq). We initially postulated that those cell lines may express only the WT allele at the RNA level although mutated at the DNA level. A more careful analysis showed that they express low level of BRAF RNA and the expression may be in favor of the WT allele. We tested whether the discordant cell lines responded differently to BRAF-specific inhibitors. Their proliferation rate decreased after treatment with vemurafenib and PLX4720 but was not affected by sorafenib, suggesting a BRAF V600E biological behavior. Yet, responsiveness to the BRAF specific inhibitors was lower as compared to the control. Western Blot analysis revealed a decreased expression of p-ERK protein in the BRAF V600E control cell line and in the discordant cell lines upon treatment with BRAF-specific inhibitors. The discordant cell lines showed a lower responsiveness to BRAF inhibitors when compared to the BRAF V600E control cell line. The results obtained from the inhibition experiment and molecular analyses were also confirmed in three additional cell lines.ConclusionCell lines carrying V600E mutation at the DNA level may respond differently to BRAF targeted treatment potentially due to a lower V600E RNA expression.
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Project description:BackgroundApproximately one third of women who develop melanoma at childbearing age are diagnosed during gestation or the postpartum period, facing pregnancy-associated melanoma (PAM). However, only some retrospective studies with heterogeneous data have analyzed the impact of pregnancy on melanoma development, and no evidence exists about the behavior and the management of BRAF-mutated disease.Subjects, materials, and methodsIn order to better describe the evolution of BRAF V600E-mutated PAM, we present here all consecutive cases diagnosed in our site during the last 7 years, recording oncological, obstetrical, and perinatal parameters, as well as the therapeutic decisions for both melanoma and gestation. Based on our institutional experience, we weigh the current published evidence and discuss upcoming clinical considerations about the prognosis of PAM, the role of BRAF status, and the possible treatment options during pregnancy in localized or advanced/metastatic disease. Five women were diagnosed with newly metastatic or relapsed BRAF V600E-mutated PAM (four during gestation and one in the 1st year postpartum) between 2012 and 2019. All of them developed extensive metastatic disease with multiple organ involvement, and four developed brain metastases. All cases experienced melanoma progression in less than 6 months under targeted therapy and died soon independently of the followed sequence of treatments. All the neonates were delivered alive and healthy, but one developed melanoma earlier than the second year of life.ResultsReviewing the literature to confirm our unfavorable outcomes, no specific data on BRAF-mutated PAM were retrieved and current evidence still supports that the prognosis of PAM should be guided by the established risk factors, whereas the management of advanced/metastatic PAM should be evaluated on a case-by-case basis.ConclusionMore data are required to ascertain whether BRAF-mutated profile adversely affects PAM outcome, although the clinicians should be aware to detect any potential melanoma lesion during pregnancy as soon as possible, treating it locally, regardless of its BRAF status.Implications for practiceThe prognosis and management of pregnancy-associated melanoma whether BRAF-mutated or wild type, is currently guided by the same parameters as in the nonpregnant condition. In this special nontrial subpopulation, BRAF-mutated status seems to have a detrimental effect on disease outcome, independently of the following treatments. In early stage melanoma, wide local excision with or without sentinel lymph node dissection may be curative at any trimester of gestation, while in advanced/metastatic setting, therapeutic strategy including immune-checkpoint or BRAF/MEK inhibitors, is more challenging, regardless of BRAF status, and should be based on an individualized decision in each case at a multidisciplinary level.
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Project description:Almost 50% of metastatic melanoma patients harbor a BRAF(V600) mutation and the introduction of BRAF inhibitors has improved their treatment options. BRAF inhibitors vemurafenib and dabrafenib achieved improved overall survival over chemotherapy and have been approved for the treatment of BRAF-mutated metastatic melanoma. However, most patients develop mechanisms of acquired resistance and about 15% of them do not achieve tumor regression at all, due to intrinsic resistance to therapy. Moreover, early adaptive responses limit the initial efficacy of BRAF inhibition, leading mostly to incomplete responses that may favor the selection of a sub-population of resistant clones and the acquisition of alterations that cause tumor regrowth and progressive disease. The purpose of this paper is to review the mechanisms of resistance to therapy with BRAF inhibitors and to discuss the strategies to overcome them based on pre-clinical and clinical evidences.
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Project description:BackgroundThe identification of somatic mutations in the gene encoding the serine-threonine protein kinase B-RAF (BRAF) in the majority of melanomas offers an opportunity to test oncogene-targeted therapy for this disease.MethodsWe conducted a multicenter, phase 1, dose-escalation trial of PLX4032 (also known as RG7204), an orally available inhibitor of mutated BRAF, followed by an extension phase involving the maximum dose that could be administered without adverse effects (the recommended phase 2 dose). Patients received PLX4032 twice daily until they had disease progression. Pharmacokinetic analysis and tumor-response assessments were conducted in all patients. In selected patients, tumor biopsy was performed before and during treatment to validate BRAF inhibition.ResultsA total of 55 patients (49 of whom had melanoma) were enrolled in the dose-escalation phase, and 32 additional patients with metastatic melanoma who had BRAF with the V600E mutation were enrolled in the extension phase. The recommended phase 2 dose was 960 mg twice daily, with increases in the dose limited by grade 2 or 3 rash, fatigue, and arthralgia. In the dose-escalation cohort, among the 16 patients with melanoma whose tumors carried the V600E BRAF mutation and who were receiving 240 mg or more of PLX4032 twice daily, 10 had a partial response and 1 had a complete response. Among the 32 patients in the extension cohort, 24 had a partial response and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months.ConclusionsTreatment of metastatic melanoma with PLX4032 in patients with tumors that carry the V600E BRAF mutation resulted in complete or partial tumor regression in the majority of patients. (Funded by Plexxikon and Roche Pharmaceuticals.)
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