BRAF inhibitors: From the laboratory to clinical trials (original) (raw)
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Targeting Oncogenic BRAF: Past, Present, and Future
Cancers
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.
The Role of BRAF Gene in Cancer: Literature Review and Future Directions
Journal of Cancer Research Updates, 2020
The BRAF gene encodes a protein belonging to the RAF family of serine/threonine protein kinases. This protein plays an important role in regulating the MAP kinase signaling pathway, which is involved in cellular development, differentiation, division, proliferation, secretion, inflammatory responses and apoptosis in mammalian cells. Since 2002, the mutation of valine 600 to glutamic acid (V600E) is the most prevalent, and it is found to be recurrent in many cancer types. It is frequently identified cancer-causing mutation in melanoma, colorectal cancer, thyroid carcinoma, non-small cell lung carcinoma, hairy cell leukemia, non-Hodgkin lymphoma, glioneuronal tumors, hepatocellular carcinoma, adenocarcinoma of lung, ovarian cancer, and also others malignancies and some cancer metastasis. In the early 1990s, some researchers began studying MAP kinase signaling pathway involved in controlling cell growth and its role in cancer, and it helped identify targets for new classes of cancer therapy. Later BRAF mutation was found in over 50% of melanomas. The overactive BRAF protein expression looked like an attractive drug target. Elucidating the detailed molecular structure of the mutant protein helped pharmaceutical companies developed selective inhibitors of mutated BRAF, including Vemurafenib and Dabrafenib, which have been approved to treat melanoma by the Food and Drug Administration (FDA). In addition, there is a growing number of targeted agents that are being evaluated to treat various BRAF-mutant advanced cancer (especially melanoma, lung, thyroid and colorectal cancer), including other RAF kinase inhibitors and/or MEK inhibitors. The standard therapy of inhibition of BRAF mutation in advanced melanoma and/or others malignancies, improved clinical benefit compared to chemotherapy. In the meantime, intrinsic and acquired resistances are still key challenges by using these drugs. The future research is heading to understand the mechanisms of the resistance, therefore it will help us to understand diseases biology and continuously bringing new therapeutic strategies for melanoma and/or others malignancies, including other drugs combination and next-generation of BRAF inhibitors.
Challenges and Opportunities in the Crusade of BRAF Inhibitors: From 2002 to 2022
ACS Omega, 2023
Serine/threonine-protein kinase B-Raf (BRAF; RAF = rapidly accelerated fibrosarcoma) plays an important role in the mitogen-activated protein kinase (MAPK) signaling cascade. Somatic mutations in the BRAF gene were first discovered in 2002 by Davies et al., which was a major breakthrough in cancer research. Subsequently, three different classes of BRAF mutants have been discovered. This class includes class I monomeric mutants (BRAF V600), class II BRAF homodimer mutants (non-V600), and class III BRAF heterodimers (non-V600). Cancers caused by these include melanoma, thyroid cancer, ovarian cancer, colorectal cancer, nonsmall cell lung cancer, and others. In this study, we have highlighted the major binding pockets in BRAF protein, their active and inactive conformations with inhibitors, and BRAF dimerization and its importance in paradoxical activation and BRAF mutation. We have discussed the first-, second-, and third-generation drugs approved by the Food and Drug Administration and drugs under clinical trials with all four different binding approaches with DFG-IN/OUT and αC-IN/ OUT for BRAF protein. We have investigated particular aspects and difficulties with all three generations of inhibitors. Finally, this study has also covered recent developments in synthetic BRAF inhibitors (from their discovery in 2002 to 2022), their unique properties, and importance in inhibiting BRAF mutants.
The multifaceted anti-cancer effects of BRAF-inhibitors
Oncotarget
The BRAF gene is commonly involved in normal processes of cell growth and differentiation. The BRAF (V600E) mutation is found in several human cancer, causing an increase of cell proliferation due to a modification of the ERK/MAPK-signal cascade. In particular, BRAFV600E mutation is found in those melanoma or thyroid cancer refractory to the common therapy and with a more aggressive phenotype. BRAF V600E was found to influence the composition of the so-called tumour microenvironment modulating both solid (immune-cell infiltration) and soluble (chemokines) mediators, which balance characterize the ultimate behaviour of the tumour, making it more or less aggressive. In particular, the presence of BRAFV600E mutation would be associated with a change of this balance to a more aggressive phenotype of the tumour and a worse prognosis. The investigation of the possible modulation of those components of tumour microenvironment is nowadays object of several studies as a new potential target therapy in those more complicated cases. At present several clinical trials both in melanoma and thyroid cancer are using BRAF-inhibitors with encouraging results, which are derived also from numerous in vitro pre-clinical studies aimed at evaluate the possible modulation of immune-cell density and of specific protumorigenic chemokine secretion (CXCL8 and CCL2) by several BRAF-inhibitors in the context of melanoma and thyroid cancer. This review will encompass in vitro and in vivo studies which investigated the modulation of the tumour microenvironment by BRAF-inhibitors, highlighting also the most recent clinical trials with a specific focus on melanoma and thyroid cancer.
BRAF mutant non-small cell lung cancer and treatment with BRAF inhibitors
Translational lung cancer research, 2013
Inhibitors targeting active protein kinases, such as EGFR or ALK, have demonstrated significant efficacy in the treatment of lung cancer. Activating mutations in the MAPK pathway, which includes the enzymes RAS, RAF, MEK, and ERK, result in constitutive signalling, leading to oncogenic cell proliferation and escape from apoptosis; therefore this pathway is a focus of crucial interest for the development of cancer drugs. In melanoma, the most commonly mutated gene is BRAF, with mutations usually occurring in about 50% of all tumours. The BRAF Val600Glu (V600E) mutation constitutes more than 90% of mutations in melanoma. V600E BRAF mutation shows a great dependency on MEK activity, and offers a rational therapeutic strategy for this genetically defined tumour subtype. The use of vemurafenib and dabrafenib, agents that block MAPK signaling in patients with melanoma and the BRAF V600E mutation, has been associated with prolonged survival and progression-free survival. The frequency of V...
Small molecule inhibitors of BRAF in clinical trials
Bioorganic & Medicinal Chemistry Letters, 2012
Over the last few years, BRAF has emerged as a validated target in melanoma. This review summarises recent advances in the development of BRAF inhibitors, focussing on agents that have been assessed clinically.
BRAF Mutations in Advanced Cancers: Clinical Characteristics and Outcomes
PLoS ONE, 2011
Background: Oncogenic BRAF mutations have been found in diverse malignancies and activate RAF/MEK/ERK signaling, a critical pathway of tumorigenesis. We examined the clinical characteristics and outcomes of patients with mutant (mut) BRAF advanced cancer referred to phase 1 clinic.
Cancer Research, 2006
Oncogenic BRAF alleles are both necessary and sufficient for cellular transformation, suggesting that chemical inhibition of the activated mutant protein kinase may reverse the tumor phenotype. Here, we report the characterization of SB-590885, a novel triarylimidazole that selectively inhibits Raf kinases with more potency towards B-Raf than c-Raf. Crystallographic analysis revealed that SB-590885 stabilizes the oncogenic B-Raf kinase domain in an active configuration, which is distinct from the previously reported mechanism of action of the multi-kinase inhibitor, BAY43-9006. Malignant cells expressing oncogenic B-Raf show selective inhibition of mitogen-activated protein kinase activation, proliferation, transformation, and tumorigenicity when exposed to SB-590885, whereas other cancer cell lines and normal cells display variable sensitivities or resistance to similar treatment. These studies support the validation of oncogenic B-Raf as a target for cancer therapy and provide the...
Molecular Cancer Therapeutics, 2012
Mutations in the BRAF gene have been identified in approximately 7% of cancers, including 60% to 70% of melanomas, 29% to 83% of papillary thyroid carcinomas, 4% to 16% colorectal cancers, and a lesser extent in serous ovarian and non-small cell lung cancers. The V600E mutation is found in the vast majority of cases and is an activating mutation, conferring transforming and immortalization potential to cells. CEP-32496 is a potent BRAF inhibitor in an in vitro binding assay for mutated BRAF V600E (K d BRAF V600E ¼ 14 nmol/L) and in a mitogen-activated protein (MAP)/extracellular signal-regulated (ER) kinase (MEK) phosphorylation (pMEK) inhibition assay in human melanoma (A375) and colorectal cancer (Colo-205) cell lines (IC 50 ¼ 78 and 60 nmol/L). In vitro, CEP-32496 has multikinase binding activity at other cancer targets of interest; however, it exhibits selective cellular cytotoxicity for BRAF V600E versus wild-type cells. CEP-32496 is orally bioavailable in multiple preclinical species (>95% in rats, dogs, and monkeys) and has single oral dose pharmacodynamic inhibition (10-55 mg/kg) of both pMEK and pERK in BRAF V600E colon carcinoma xenografts in nude mice. Sustained tumor stasis and regressions are observed with oral administration (30-100 mg/kg twice daily) against BRAF V600E melanoma and colon carcinoma xenografts, with no adverse effects. Little or no epithelial hyperplasia was observed in rodents and primates with prolonged oral administration and sustained exposure. CEP-32496 benchmarks favorably with respect to other kinase inhibitors, including RAF-265 (phase I), sorafenib, (approved), and vemurafenib (PLX4032/ RG7204, approved). CEP-32496 represents a novel and pharmacologically active BRAF inhibitor with a favorable side effect profile currently in clinical development. Mol Cancer Ther; 11(4); 930-41. Ó2012 AACR.