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13 pages, 3011 KiB

Open AccessArticle

BRAF Mutations Classes I, II, and III in NSCLC Patients Included in the SLLIP Trial: The Need for a New Pre-Clinical Treatment Rationale

by Jillian Wilhelmina Paulina Bracht, Niki Karachaliou, Trever Bivona, Richard B. Lanman, Iris Faull, Rebecca J. Nagy, Ana Drozdowskyj, Jordi Berenguer, Manuel Fernandez-Bruno, Miguel Angel Molina-Vila and Rafael Rosell

Cancers 2019, 11(9), 1381; https://doi.org/10.3390/cancers11091381 - 17 Sep 2019

Cited by 49 | Viewed by 10322

Abstract

BRAF V600 mutations have been found in 1–2% of non-small-cell lung cancer (NSCLC) patients, with Food and Drug Administration (FDA) approved treatment of dabrafenib plus trametinib and progression free survival (PFS) of 10.9 months. However, 50–80% of BRAF mutations in lung cancer are [...] Read more.

BRAF V600 mutations have been found in 1–2% of non-small-cell lung cancer (NSCLC) patients, with Food and Drug Administration (FDA) approved treatment of dabrafenib plus trametinib and progression free survival (PFS) of 10.9 months. However, 50–80% of BRAF mutations in lung cancer are non-V600, and can be class II, with intermediate to high kinase activity and RAS independence, or class III, with impaired kinase activity, upstream signaling dependence, and consequently, sensitivity to receptor tyrosine kinase (RTK) inhibitors. Plasma cell-free DNA (cfDNA) of 185 newly diagnosed advanced lung adenocarcinoma patients (Spanish Lung Liquid versus Invasive Biopsy Program, SLLIP, NCT03248089) was examined for BRAF and other alterations with a targeted cfDNA next-generation sequencing (NGS) assay (Guardant360®, Guardant Health Inc., CA, USA), and results were correlated with patient outcome. Cell viability with single or combined RAF, MEK, and SHP2 inhibitors was assessed in cell lines with BRAF class I, II, and III mutations. Out of 185 patients, 22 had BRAF alterations (12%) of which seven patients harbored amplifications (32%) and 17 had BRAF mutations (77%). Of the BRAF mutations, four out of 22 (18%) were V600E and 18/22 (82%) were non-V600. In vitro results confirmed sensitivity of class III and resistance of class I and II BRAF mutations, and BRAF wild type cells to SHP2 inhibition. Concomitant MEK or RAF and SHP2 inhibition showed synergistic effects, especially in the class III BRAF-mutant cell line. Our study indicates that the class of the BRAF mutation may have clinical implications and therefore should be defined in the clinical practice and used to guide therapeutic decisions. Full article

(This article belongs to the Special Issue Oncogenic Forms of BRAF as Cancer Driver Genes)

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15 pages, 903 KiB

Open AccessArticle

BRAF Mutation in Colorectal Rhabdoid and Poorly Differentiated Medullary Carcinomas

by Elena Bolzacchini, Nunzio Digiacomo, Cristina Marrazzo, Nora Sahnane, Roberta Maragliano, Anthony Gill, Luca Albarello, Fausto Sessa, Daniela Furlan and Carlo Capella

Cancers 2019, 11(9), 1252; https://doi.org/10.3390/cancers11091252 - 26 Aug 2019

Cited by 4 | Viewed by 2948

Abstract

Colorectal rhabdoid carcinomas (CRbCs) are very rare and aggressive cancers. The BRAF mutation and CpG island methylator phenotype have been reported to be common features of CRbCs. This study reviews the literature about CRbCs and analyzes the clinicopathological and molecular profiles of seven [...] Read more.

Colorectal rhabdoid carcinomas (CRbCs) are very rare and aggressive cancers. The BRAF mutation and CpG island methylator phenotype have been reported to be common features of CRbCs. This study reviews the literature about CRbCs and analyzes the clinicopathological and molecular profiles of seven CRbCs characterized by large discohesive cells with abundant eosinophilic cytoplasm, showing hyaline inclusions and large rounded to bean-shaped nuclei. For comparison, we included four poorly differentiated medullary carcinomas (PDMCs) with focal aspects mimicking rhabdoid features. Overall survival was poor in both subsets, with 78% of patients dying of disease within 2–11 months. The main features of CRbCs were: Loss of/reduced SMARCB1/INI expression, intense vimentin immunostaining, and dense neutrophilic infiltration. The PDMCs were positive for pancytokeratin but negative for vimentin and showed moderate peritumoral/intratumoral CD8+ lymphocytes. All PDMCs showed SMARCB1(INI-1) expression. The coexistence of BRAF and TP53 mutations was observed in 80% of CRbCs and PDMCs. PDMCs always showed microsatellite instability and CpG island methylator phenotype (CIMP), while CRbCs were CIMP negative and exhibited microsatellite instability (MSI) in two out of seven cases. CRbCs are characterized by BRAF and TP53 mutations. Loss/reduced expression of nuclear SMARCB1/INI, intense vimentin immunostaining, dense neutrophilic infiltration, and low frequency of CIMP are useful markers to recognize these rare aggressive tumors. Full article

(This article belongs to the Special Issue Oncogenic Forms of BRAF as Cancer Driver Genes)

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16 pages, 2022 KiB

Open AccessArticle

Baseline Genomic Features in BRAFV600-Mutated Metastatic Melanoma Patients Treated with BRAF Inhibitor + MEK Inhibitor in Routine Care

by Baptiste Louveau, Fanelie Jouenne, Coralie Reger de Moura, Aurelie Sadoux, Barouyr Baroudjian, Julie Delyon, Florian Herms, Adele De Masson, Laetitia Da Meda, Maxime Battistella, Nicolas Dumaz, Celeste Lebbe and Samia Mourah

Cancers 2019, 11(8), 1203; https://doi.org/10.3390/cancers11081203 - 18 Aug 2019

Cited by 9 | Viewed by 3052

Abstract

In BRAF^V600mut metastatic melanoma, the combination of BRAF and MEK inhibitors (BRAFi, MEKi) has undergone multiple resistance mechanisms, limiting its clinical benefit and resulting in the need for response predicting biomarkers. Based on phase III clinical trial data, several studies have previously [...] Read more.

In BRAF^V600mut metastatic melanoma, the combination of BRAF and MEK inhibitors (BRAFi, MEKi) has undergone multiple resistance mechanisms, limiting its clinical benefit and resulting in the need for response predicting biomarkers. Based on phase III clinical trial data, several studies have previously explored baseline genomic features associated with response to BRAFi + MEKi. Using a targeted approach that combines the examination of mRNA expression and DNA alterations in a subset of genes, we performed an analysis of baseline genomic alterations involved in MAPK inhibitors’ resistance in a real-life cohort of BRAF^V600mut metastatic melanoma patients. Twenty-seven patients were included in this retrospective study, and tumor samples were analyzed when the BRAFi + MEKi therapy was initiated. The clinical characteristics of our cohort were consistent with previously published studies. The BRAFi + MEKi treatment was initiated in seven patients as a following-line treatment, and had a specific transcriptomic profile exhibiting 14 genes with lower mRNA expression. However, DNA alterations in CCND1, RB1, and MET were only observed in patients who received BRAFi + MEKi as the first-line treatment. Furthermore, KIT mRNA expression was significantly higher in patients showing clinical benefit from the combined therapy, emphasizing the tumor-suppressor role of KIT already described within the context of BRAF-mutant melanoma. Full article

(This article belongs to the Special Issue Oncogenic Forms of BRAF as Cancer Driver Genes)

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Review

Jump to: Research

20 pages, 829 KiB

Open AccessReview

Epigenetic Mechanisms of Escape from BRAF Oncogene Dependency

by Mehwish Khaliq and Mohammad Fallahi-Sichani

Cancers 2019, 11(10), 1480; https://doi.org/10.3390/cancers11101480 - 01 Oct 2019

Cited by 26 | Viewed by 4945

Abstract

About eight percent of all human tumors (including 50% of melanomas) carry gain-of-function mutations in the BRAF oncogene. Mutated BRAF and subsequent hyperactivation of the MAPK signaling pathway has motivated the use of MAPK-targeted therapies for these tumors. Despite great promise, however, MAPK-targeted [...] Read more.

About eight percent of all human tumors (including 50% of melanomas) carry gain-of-function mutations in the BRAF oncogene. Mutated BRAF and subsequent hyperactivation of the MAPK signaling pathway has motivated the use of MAPK-targeted therapies for these tumors. Despite great promise, however, MAPK-targeted therapies in BRAF-mutant tumors are limited by the emergence of drug resistance. Mechanisms of resistance include genetic, non-genetic and epigenetic alterations. Epigenetic plasticity, often modulated by histone-modifying enzymes and gene regulation, can influence a tumor cell’s BRAF dependency and therefore, response to therapy. In this review, focusing primarily on class 1 BRAF-mutant cells, we will highlight recent work on the contribution of epigenetic mechanisms to inter- and intratumor cell heterogeneity in MAPK-targeted therapy response. Full article

(This article belongs to the Special Issue Oncogenic Forms of BRAF as Cancer Driver Genes)

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14 pages, 543 KiB

Open AccessReview

Significance of BRAF Kinase Inhibitors for Melanoma Treatment: From Bench to Bedside

by Taku Fujimura, Yasuhiro Fujisawa, Yumi Kambayashi and Setsuya Aiba

Cancers 2019, 11(9), 1342; https://doi.org/10.3390/cancers11091342 - 11 Sep 2019

Cited by 19 | Viewed by 3534

Abstract

According to clinical trials, BRAF kinase inhibitors in combination with MEK kinase inhibitors are among the most promising chemotherapy regimens for the treatment of advanced BRAF-mutant melanoma, though the rate of BRAF mutation gene-bearing cutaneous melanoma is limited, especially in the Asian population. [...] Read more.

According to clinical trials, BRAF kinase inhibitors in combination with MEK kinase inhibitors are among the most promising chemotherapy regimens for the treatment of advanced BRAF-mutant melanoma, though the rate of BRAF mutation gene-bearing cutaneous melanoma is limited, especially in the Asian population. In addition, drug resistance sometimes abrogates the persistent efficacy of combined therapy with BRAF and MEK inhibitors. Therefore, recent pre-clinical study-based clinical trials have attempted to identify optimal drugs (e.g., immune checkpoint inhibitors or histone deacetylase (HDAC) inhibitors) that improve the anti-melanoma effects of BRAF and MEK inhibitors. In addition, the development of novel protocols to avoid resistance of BRAF inhibitors is another purpose of recent pre-clinical and early clinical trials. This review focuses on pre-clinical studies and early to phase III clinical trials to discuss the development of combined therapy based on BRAF inhibitors for BRAF-mutant advanced melanoma, as well as mechanisms of resistance to BRAF inhibitors. Full article

(This article belongs to the Special Issue Oncogenic Forms of BRAF as Cancer Driver Genes)

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18 pages, 562 KiB

Open AccessFeature PaperReview

BRAF Mutations and the Utility of RAF and MEK Inhibitors in Primary Brain Tumors

by Karisa C. Schreck, Stuart A. Grossman and Christine A. Pratilas

Cancers 2019, 11(9), 1262; https://doi.org/10.3390/cancers11091262 - 28 Aug 2019

Cited by 89 | Viewed by 8544

Abstract

BRAF mutations have been identified as targetable, oncogenic mutations in many cancers. Given the paucity of treatments for primary brain tumors and the poor prognosis associated with high-grade gliomas, BRAF mutations in glioma are of considerable interest. In this review, we present the [...] Read more.

BRAF mutations have been identified as targetable, oncogenic mutations in many cancers. Given the paucity of treatments for primary brain tumors and the poor prognosis associated with high-grade gliomas, BRAF mutations in glioma are of considerable interest. In this review, we present the spectrum of BRAF mutations and fusion alterations present in each class of primary brain tumor based on publicly available databases and publications. We also summarize clinical experience with RAF and MEK inhibitors in patients with primary brain tumors and describe ongoing clinical trials of RAF inhibitors in glioma. Sensitivity to RAF and MEK inhibitors varies among BRAF mutations and between tumor types as only class I BRAF V600 mutations are sensitive to clinically available RAF inhibitors. While class II and III BRAF mutations are found in primary brain tumors, further research is necessary to determine their sensitivity to third-generation RAF inhibitors and/or MEK inhibitors. We recommend that the neuro-oncologist consider using these drugs primarily in the setting of a clinical trial for patients with BRAF-altered glioma in order to advance our knowledge of their efficacy in this patient population. Full article

(This article belongs to the Special Issue Oncogenic Forms of BRAF as Cancer Driver Genes)

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19 pages, 1610 KiB

Open AccessReview

Targeting Oncogenic BRAF: Past, Present, and Future

by Aubhishek Zaman, Wei Wu and Trever G. Bivona

Cancers 2019, 11(8), 1197; https://doi.org/10.3390/cancers11081197 - 16 Aug 2019

Cited by 137 | Viewed by 10487

Abstract

Identifying recurrent somatic genetic alterations of, and dependency on, the kinase BRAF has enabled a “precision medicine” paradigm to diagnose and treat BRAF-driven tumors. Although targeted kinase inhibitors against BRAF are effective in a subset of mutant BRAF tumors, resistance to the therapy [...] Read more.

Identifying recurrent somatic genetic alterations of, and dependency on, the kinase BRAF has enabled a “precision medicine” paradigm to diagnose and treat BRAF-driven tumors. Although targeted kinase inhibitors against BRAF are effective in a subset of mutant BRAF tumors, resistance to the therapy inevitably emerges. In this review, we discuss BRAF biology, both in wild-type and mutant settings. We discuss the predominant BRAF mutations and we outline therapeutic strategies to block mutant BRAF and cancer growth. We highlight common mechanistic themes that underpin different classes of resistance mechanisms against BRAF-targeted therapies and discuss tumor heterogeneity and co-occurring molecular alterations as a potential source of therapy resistance. We outline promising therapy approaches to overcome these barriers to the long-term control of BRAF-driven tumors and emphasize how an extensive understanding of these themes can offer more pre-emptive, improved therapeutic strategies. Full article

(This article belongs to the Special Issue Oncogenic Forms of BRAF as Cancer Driver Genes)

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18 pages, 2533 KiB

Open AccessReview

Adaptive Responses as Mechanisms of Resistance to BRAF Inhibitors in Melanoma

by Azad Saei and Pieter Johan Adam Eichhorn

Cancers 2019, 11(8), 1176; https://doi.org/10.3390/cancers11081176 - 14 Aug 2019

Cited by 20 | Viewed by 5842

Abstract

The introduction of v-raf murine sarcoma viral oncogene homolog B (BRAF) inhibitors in melanoma patients with BRAF (V600E) mutations has demonstrated significant clinical benefits. However, rarely do tumours regress completely. Frequently, the reason for this is that therapies targeting specific oncogenic mutations induce [...] Read more.

The introduction of v-raf murine sarcoma viral oncogene homolog B (BRAF) inhibitors in melanoma patients with BRAF (V600E) mutations has demonstrated significant clinical benefits. However, rarely do tumours regress completely. Frequently, the reason for this is that therapies targeting specific oncogenic mutations induce a number of intrinsic compensatory mechanisms, also known as adaptive responses or feedback loops, that enhance the pro-survival and pro-proliferative capacity of a proportion of the original tumour population, thereby resulting in tumour progression. In this review we will summarize the known adaptive responses that limit BRAF mutant therapy and discuss potential novel combinatorial therapies to overcome resistance. Full article

(This article belongs to the Special Issue Oncogenic Forms of BRAF as Cancer Driver Genes)

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13 pages, 2497 KiB

Open AccessReview

Atypical BRAF and NRAS Mutations in Mucosal Melanoma

by Nicolas Dumaz, Fanélie Jouenne, Julie Delyon, Samia Mourah, Armand Bensussan and Céleste Lebbé

Cancers 2019, 11(8), 1133; https://doi.org/10.3390/cancers11081133 - 08 Aug 2019

Cited by 45 | Viewed by 8122

Abstract

Primary mucosal melanomas represent a minority of melanomas, but have a significantly worse prognosis than cutaneous melanomas. A better characterization of the molecular pathogenesis of this melanoma subtype could help us understand the risk factors associated with the development of mucosal melanomas and [...] Read more.

Primary mucosal melanomas represent a minority of melanomas, but have a significantly worse prognosis than cutaneous melanomas. A better characterization of the molecular pathogenesis of this melanoma subtype could help us understand the risk factors associated with the development of mucosal melanomas and highlight therapeutic targets. Because the Mitogen-Activated Protein Kinase (MAPK) pathway plays such a significant role in melanoma development, we explore v-raf murine sarcoma viral oncogene homolog B (BRAF) and neuroblastoma RAS viral oncogene homolog (NRAS) mutations in mucosal melanoma and compare them to the mutation profiles in cutaneous melanoma and other tumors with BRAF and NRAS mutations. We show that in addition to being less frequent, BRAF and NRAS mutations are different in mucosal melanoma compared to cutaneous melanomas. Strikingly, the BRAF and NRAS mutation profiles in mucosal melanoma are closer to those found in cancers such as lung cancer, suggesting that mutations in mucosal melanoma could be linked to some genotoxic agents that remain to be identified. We also show that the atypical BRAF and NRAS mutations found in mucosal melanomas have particular effects on protein activities, which could be essential for the transformation of mucosal melanocytes. Full article

(This article belongs to the Special Issue Oncogenic Forms of BRAF as Cancer Driver Genes)

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16 pages, 1160 KiB

Open AccessReview

Oncogenic BRAF Alterations and Their Role in Brain Tumors

by Felix Behling and Jens Schittenhelm

Cancers 2019, 11(6), 794; https://doi.org/10.3390/cancers11060794 - 08 Jun 2019

Cited by 57 | Viewed by 10566

Abstract

Alterations of the v-raf murine sarcoma viral oncogene homolog B (BRAF) have been extensively studied in several tumor entities and are known to drive cell growth in several tumor entities. Effective targeted therapies with mutation-specific small molecule inhibitors have been developed and established [...] Read more.

Alterations of the v-raf murine sarcoma viral oncogene homolog B (BRAF) have been extensively studied in several tumor entities and are known to drive cell growth in several tumor entities. Effective targeted therapies with mutation-specific small molecule inhibitors have been developed and established for metastasized malignant melanoma. The BRAF V600E mutation and KIAA1549-BRAF fusion are alterations found in several brain tumors and show a distinct prognostic impact in some entities. Besides the diagnostic significance for the classification of central nervous system tumors, these alterations present possible therapy targets that may be exploitable for oncological treatments, as it has been established for malignant melanomas. In this review the different central nervous system tumors harboring BRAF alterations are presented and the diagnostic significance, prognostic role, and therapeutic potential are discussed. Full article

(This article belongs to the Special Issue Oncogenic Forms of BRAF as Cancer Driver Genes)

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