azd-6244 and dabrafenib

New treatments for metastatic melanoma work through distinct mechanisms: enhancing the immune response and blocking cellular proliferation. Agents that enhance the immune response include ipilimumab, pembrolizumb, and nivolumab; agents that block cellular proliferation include vemurafenib, dabrafenib, trametinib, cobimetinib, binimetinib, and selumetinib. The translational impact of laboratory discoveries has revolutionized management of metastatic melanoma and enhanced the prognosis of affected patients.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Benzimidazoles; Humans; Imidazoles; Immunologic Factors; Indoles; Ipilimumab; Melanoma; Molecular Targeted Therapy; Nivolumab; Oximes; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Vemurafenib

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Drug Discovery; Humans; Imidazoles; Indoles; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; Molecular Targeted Therapy; Neoplasms; Oximes; Pyridones; Pyrimidinones; raf Kinases; Research; Sulfonamides; Vemurafenib

Clinical efficacy of differentiation therapy with mitogen-activated protein kinase inhibitors (MAPKi) for lethal radioiodine-refractory papillary thyroid cancer (RR-PTC) urgently needs to be improved and the aberrant trimethylation of histone H3 lysine 27 (H3K27) plays a vital role in BRAF

Topics: Benzamides; Benzimidazoles; Biphenyl Compounds; Cell Differentiation; Cell Line, Tumor; Drug Resistance, Neoplasm; Enhancer of Zeste Homolog 2 Protein; Gene Expression Regulation, Neoplastic; Histones; Humans; Imidazoles; Iodine Radioisotopes; Methylation; Mitogen-Activated Protein Kinases; Morpholines; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Thyroid Cancer, Papillary; Thyroid Gland

Redifferentiation therapy with BRAF/MEK inhibitors to facilitate treatment with radioiodine represents a good choice for radioiodine-refractory differentiated thyroid carcinoma, but recent initial clinical outcomes were modest. MAPK rebound caused by BRAF/MEK inhibitors-induced activation of HER2/HER3 is a resistance mechanism, and combination with HER inhibitor to prevent MAPK rebound may sensitize BRAFV600E-mutant thyroid cancer cells to redifferentiation therapy. To evaluate if inhibiting both BRAF/MEK and HER can produce stronger redifferetiation effect, we tested the effects of BRAF/MEK inhibitor dabrafenib/selumetinib alone or in combination with HER inhibitor lapatinib on the expression and function of iodine- and glucose-handling genes in BRAFV600E-positive BCPAP and K1 cells, using BHP 2-7 cells harboring RET/PTC1 rearrangement as control. Herein, we showed that lapatinib prevented MAPK rebound and sensitized BRAFV600E-positive papillary thyroid cancer cells to BRAF/MEK inhibitors. Dabrafenib/selumetinib alone increased iodine-uptake and toxicity and suppressed glucose-metablism in BRAFV600E-positive papillary thyroid cancer cells. When lapatinib was added, more significant effects on iodine- and glucose-handling gene expression, cell membrane location of sodium/iodine symporter as well as radioiodine uptake and toxicity were observed. Thus, combined therapy using HER inhibitor and BRAF/MEK inhibitor presented more significant redifferentiation effect on papillary thyroid cancer cells harboring BRAFV600E than BRAF/MEK inhibitor alone. In vivo and clinical studies assessing such combined targeted redifferentiation strategy were warranted.

Topics: Benzimidazoles; Blotting, Western; Carcinoma, Papillary; Cell Cycle; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Humans; Imidazoles; Inhibitory Concentration 50; Lapatinib; MAP Kinase Kinase 1; Microscopy, Fluorescence; Mutation, Missense; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Quinazolines; Receptor, ErbB-2; Reverse Transcriptase Polymerase Chain Reaction; Thyroid Neoplasms

While clinical and radiographic responses to agents targeting the mitogen-activated protein kinases (MAPK) pathway have been repor-ted in pediatric low-grade gliomas (LGG), early phase trials indicate refractoriness to these medications in some of these patients. We report a patient with disseminated LGG with the BRAFV600E mutation, which was refractory to selumetinib, a MEK inhibitor, but subsequently showed immediate clinical and radiographic response to dabrafenib, a BRAF inhibitor, with sustained effect for 9 months prior to clinical progression. In LGGs, treatment resistance to one agent targeting the MAPK pathway might not imply refractoriness to other agents targeting this pathway.

Topics: Amino Acid Substitution; Benzimidazoles; Chemoradiotherapy; Glioma; Humans; Imidazoles; Infant; Male; Mutation, Missense; Optic Nerve Neoplasms; Oximes; Proto-Oncogene Proteins B-raf

Diverse pathways drive resistance to BRAF/MEK inhibitors in BRAF-mutant melanoma, suggesting that durable control of resistance will be a challenge. By combining statistical modeling of genomic data from matched pre-treatment and post-relapse patient tumors with functional interrogation of >20 in vitro and in vivo resistance models, we discovered that major pathways of resistance converge to activate the transcription factor, c-MYC (MYC). MYC expression and pathway gene signatures were suppressed following drug treatment, and then rebounded during progression. Critically, MYC activation was necessary and sufficient for resistance, and suppression of MYC activity using genetic approaches or BET bromodomain inhibition was sufficient to resensitize cells and delay BRAFi resistance. Finally, MYC-driven, BRAFi-resistant cells are hypersensitive to the inhibition of MYC synthetic lethal partners, including SRC family and c-KIT tyrosine kinases, as well as glucose, glutamine, and serine metabolic pathways. These insights enable the design of combination therapies that select against resistance evolution.

Topics: Antineoplastic Agents, Hormonal; Benzimidazoles; Cell Line, Tumor; Estradiol; Evolution, Molecular; Female; Fulvestrant; Humans; Imidazoles; Indoles; Male; Melanoma; Oximes; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-myc; Pyridones; Pyrimidinones; Quinolines; Signal Transduction; Sulfonamides

B-Raf inhibitors have been used for the treatment of some B-Raf-mutated cancers. They effectively inhibit B-Raf/MEK/ERK signaling in cancers harboring mutant B-Raf, but paradoxically activates MEK/ERK in Ras-mutated cancers. Death receptor 5 (DR5), a cell surface pro-apoptotic protein, triggers apoptosis upon ligation with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or aggregation. This study focused on determining the effects of B-Raf inhibition on DR5 expression and DR5 activation-induced apoptosis in Ras-mutant cancer cells. Using chemical and genetic approaches, we have demonstrated that the B-Raf inhibitor PLX4032 induces DR5 upregulation exclusively in Ras-mutant cancer cells; this effect is dependent on Ras/c-Raf/MEK/ERK signaling activation. PLX4032 induces DR5 expression at transcriptional levels, largely due to enhancing CHOP/Elk1-mediated DR5 transcription. Pre-exposure of Ras-mutated cancer cells to PLX4032 sensitizes them to TRAIL-induced apoptosis; this is also a c-Raf/MEK/ERK-dependent event. Collectively, our findings highlight a previously undiscovered effect of B-Raf inhibition on the induction of DR5 expression and the enhancement of DR5 activation-induced apoptosis in Ras-mutant cancer cells and hence may suggest a novel therapeutic strategy against Ras-mutated cancer cells by driving their death due to DR5-dependent apoptosis through B-Raf inhibition.

Topics: Apoptosis; Benzimidazoles; Cell Line, Tumor; Enzyme Activation; ets-Domain Protein Elk-1; Gene Expression Regulation, Neoplastic; Genes, ras; Humans; Imidazoles; Indoles; MAP Kinase Signaling System; Neoplasm Proteins; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-raf; Receptors, TNF-Related Apoptosis-Inducing Ligand; Recombinant Proteins; Sulfonamides; TNF-Related Apoptosis-Inducing Ligand; Transcription Factor CHOP; Transcription, Genetic; Vemurafenib

The aim of combination drug treatment in cancer therapy is to improve response rate and to decrease the probability of the development of drug resistance. Preferably, drug combinations are synergistic rather than additive, and, ideally, drug combinations work synergistically only in cancer cells and not in non-malignant cells. We have developed a workflow to identify such targeted synergies, and applied this approach to selectively inhibit the proliferation of cell lines with mutations in genes that are difficult to modulate with small molecules. The approach is based on curve shift analysis, which we demonstrate is a more robust method of determining synergy than combination matrix screening with Bliss-scoring. We show that the MEK inhibitor trametinib is more synergistic in combination with the BRAF inhibitor dabrafenib than with vemurafenib, another BRAF inhibitor. In addition, we show that the combination of MEK and BRAF inhibitors is synergistic in BRAF-mutant melanoma cells, and additive or antagonistic in, respectively, BRAF-wild type melanoma cells and non-malignant fibroblasts. This combination exemplifies that synergistic action of drugs can depend on cancer genotype. Next, we used curve shift analysis to identify new drug combinations that specifically inhibit cancer cell proliferation driven by difficult-to-drug cancer genes. Combination studies were performed with compounds that as single agents showed preference for inhibition of cancer cells with mutations in either the CTNNB1 gene (coding for β-catenin), KRAS, or cancer cells expressing increased copy numbers of MYC. We demonstrate that the Wnt-pathway inhibitor ICG-001 and trametinib acted synergistically in Wnt-pathway-mutant cell lines. The ERBB2 inhibitor TAK-165 was synergistic with trametinib in KRAS-mutant cell lines. The EGFR/ERBB2 inhibitor neratinib acted synergistically with the spindle poison docetaxel and with the Aurora kinase inhibitor GSK-1070916 in cell lines with MYC amplification. Our approach can therefore efficiently discover novel drug combinations that selectively target cancer genes.

Topics: Antineoplastic Combined Chemotherapy Protocols; Aza Compounds; Benzimidazoles; beta Catenin; Cell Line, Tumor; Cell Proliferation; Humans; Imidazoles; Indazoles; Indoles; Melanoma; Molecular Targeted Therapy; Mutation; Oxazoles; Oximes; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Quinolines; Sulfonamides; Triazoles; Vemurafenib

Heat shock protein (HSP)90 inhibitors have shown significant anti-tumor activities in preclinical settings in both solid and hematological tumors. We previously reported that the novel, orally available HSP90α/β inhibitor TAS-116 shows significant anti-MM activities. In this study, we further examined the combination effect of TAS-116 with a RAS-RAF-MEK-ERK signaling pathway inhibitor in RAS- or BRAF-mutated MM cell lines. TAS-116 monotherapy significantly inhibited growth of RAS-mutated MM cell lines and was associated with decreased expression of downstream target proteins of the RAS-RAF-MEK-ERK signaling pathway. Moreover, TAS-116 showed synergistic growth inhibitory effects with the farnesyltransferase inhibitor tipifarnib, the BRAF inhibitor dabrafenib, and the MEK inhibitor selumetinib. Importantly, treatment with these inhibitors paradoxically enhanced p-C-Raf, p-MEK, and p-ERK activity, which was abrogated by TAS-116. TAS-116 also enhanced dabrafenib-induced MM cytotoxicity associated with mitochondrial damage-induced apoptosis, even in the BRAF-mutated U266 MM cell line. This enhanced apoptosis in RAS-mutated MM triggered by combination treatment was observed even in the presence of bone marrow stromal cells. Taken together, our results provide the rationale for novel combination treatment with HSP90α/β inhibitor and RAS-RAF-MEK-ERK signaling pathway inhibitors to improve outcomes in patients with in RAS- or BRAF-mutated MM.

Topics: Apoptosis; Benzamides; Benzimidazoles; Bortezomib; Cell Line, Tumor; Doxorubicin; Drug Screening Assays, Antitumor; Genes, ras; HSP90 Heat-Shock Proteins; Humans; Imidazoles; MAP Kinase Signaling System; Multiple Myeloma; Oximes; Proto-Oncogene Proteins B-raf; Pyrazoles

BRAF-mutant melanoma can be successfully treated by BRAF kinase inhibitors (BRAFi) and MEK kinase inhibitors (MEKi). However, the administration of BRAFi followed by MEKi did not generate promising response rate (RR). The purpose of this investigation was to evaluate the time to progression (TTP) with a mitogen-activated protein kinase (MAPK) pathway upstream inhibition strategy in BRAF mutated melanoma patients. BRAF mutation positive metastatic melanoma patients were identified within the Dermatology Cooperative Oncology Group (DeCOG) network and were treated first with a MEKi and upon progression with a selective BRAFi. A total of 23 melanoma patients (six females, 17 males, aged 47-80 years) were retrospectively analysed for TTP. The total median TTP was 8.9 months. The median TTP for MEKi was 4.8 (1.2-23.2) and subsequent for BRAFi 4.5 (1.2-15.7) months, respectively. A higher RR for MEKi (39%, nine partial responses and 0 complete responses) than previously reported was observed. Our analysis suggests that the reversed inhibition of the MAPK pathway is feasible in BRAF mutated melanoma. The median TTP (8.9 months) is close to the promising BRAF- and MEKi combination therapy (median progression-free survival (PFS) 9.4 months). The total treatment duration of the MAPK inhibition when a MEKi is administered first is similar compared to the reversed sequence, but TTP shifts in favour to the MEKi. This approach is feasible with reasonable tolerability. This clinical investigation encourages further studies in prospective clinical trials to define the optimal treatment schedule for the MAPK pathway inhibition and should be accompanied by molecular monitoring using repeated biopsies.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Disease Progression; Disease-Free Survival; Feasibility Studies; Female; Humans; Imidazoles; Indoles; Male; MAP Kinase Signaling System; Melanoma; Middle Aged; Mitogen-Activated Protein Kinases; Mutation; Outcome Assessment, Health Care; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Sulfonamides; Time Factors; Vemurafenib