- |||||||||| S63845 / Servier, Novartis, HitGen, SCH772984 / Otsuka, Zelboraf (vemurafenib) / Roche
Journal, PARP Biomarker, IO biomarker: Enhanced Apoptosis and Loss of Cell Viability in Melanoma Cells by Combined Inhibition of ERK and Mcl-1 Is Related to Loss of Mitochondrial Membrane Potential, Caspase Activation and Upregulation of Proapoptotic Bcl-2 Proteins. (Pubmed Central) - Mar 16, 2023
The combination finally resulted in downregulation of antiapoptotic Bcl-2 and enhanced expression of the proapoptotic Noxa. In conclusion, combined inhibition of ERK and Mcl-1 revealed an impressive efficacy both in BRAF-mutated and WT melanoma cells, and may thus represent a new strategy for overcoming drug resistance.
- |||||||||| Opdivo (nivolumab) / BMS, Braftovi (encorafenib) / Pfizer, Mektovi (binimetinib) / Pfizer
Enrollment change: Adaptive BRAF-MEK Inhibitor Therapy for Advanced BRAF Mutant Melanoma (clinicaltrials.gov) - Mar 16, 2023
P1, N=10, Recruiting,
In conclusion, combined inhibition of ERK and Mcl-1 revealed an impressive efficacy both in BRAF-mutated and WT melanoma cells, and may thus represent a new strategy for overcoming drug resistance. N=20 --> 10
- |||||||||| PLX4720 / Daiichi Sankyo, AZ 628 / AstraZeneca, Zelboraf (vemurafenib) / Roche
Journal: Design, synthesis and characterisation of a novel type II B-RAF paradox breaker inhibitor. (Pubmed Central) - Mar 15, 2023
This unwanted activation may be avoided by another class of inhibitors (type II) which bind the kinase in the DFG-out conformation, such as AZ628 (3) preventing heterodimerization...We discovered that the inhibitor was active and selective for B-Raf, binds in a DFG-out/?C-helix-in conformation, and did not induce the aforementioned paradoxical hyperactivation in the MAPK pathway. We propose that this merging approach can be used to design a novel class of B-Raf inhibitors for translational studies.
- |||||||||| Iclusig (ponatinib) / Takeda, Otsuka, Incyte, Zelboraf (vemurafenib) / Roche
YAP inhibition via targeting MAP3K3-dependent lysosomal degradation pathway overcomes BRAF and CDK4/6 inhibitor resistance (Section 2; Poster Board #8) - Mar 14, 2023 - Abstract #AACR2023AACR_8805;
Accordingly, the combination of vemurafenib and ponatinib was effective in reducing the survival of BRAF inhibitor-resistant melanoma cells. Collectively, our study identified a novel phosphorylation-mediated YAP stability regulation mechanism and underscored MAP3K3 inhibition as a promising strategy to overcome BRAF and CDK4/6 inhibitor resistance by directly promoting YAP degradation.
- |||||||||| Zelboraf (vemurafenib) / Roche
A systems pharmacology approach to discover synergistic targeted therapy combinations (Section 13; Poster Board #19) - Mar 14, 2023 - Abstract #AACR2023AACR_7222;
Targeted MS of phospho-ERK1/2 and canonical SFK substrates, including CTTN, PXN, and PAG1, validated the mechanism of action of this combination. Complementary data from patient-derived non small-cell lung cancer (NSCLC) cells under tyrosine kinase inhibitor treatment demonstrates the generality of our integrative approach, and supports the notion that SFK activation may be a hallmark response to oncogenic RTK-RAS-ERK pathway inhibition.
- |||||||||| volasertib (NBL-001) / Oncoheroes, Notable Labs, Zelboraf (vemurafenib) / Roche
PLK1 promotes the metastasis and drug resistance in melanoma (Section 17; Poster Board #10) - Mar 14, 2023 - Abstract #AACR2023AACR_7173;
Our in vitro and in vivo experiments have shown an improved efficacy of this combined therapy on inhibition of cell proliferation, induction of cell death, and suppression of cell metastasis compared to mono-treatment. In short, our data has indicated PLK1 as a potent and promising target in cancer treatment.
- |||||||||| Zelboraf (vemurafenib) / Roche
Novel melanoma leads demonstrate efficacy in A375 xenograft model in nude mice (Section 30; Poster Board #26) - Mar 14, 2023 - Abstract #AACR2023AACR_6882;
Animals were then randomized into four groups to receive subcutaneous administration of vehicle, 10mg/kg vemurafenib, and 25mg/kg 2155-14 and 2155-18 three times per week for 15 days...These results are well correlated with the exposure of leads in plasma. In summary, these results suggest a therapeutic potential of targeting spliceosomal proteins hnRNPH1 and H2 and support potential of 2155-14 and 2155-18 as drug candidates for treatment of melanoma.
- |||||||||| Zelboraf (vemurafenib) / Roche
The small GTPase ARF6 augments BRAFV600E-MAPK signaling in melanomagenesis (Room W304 E-H - Convention Center) - Mar 14, 2023 - Abstract #AACR2023AACR_5612;
Overall, our data reveal that ARF6 augments MAPK signaling in BRAFV600E-driven tumorigenesis. Further work is needed to understand if ARF6 mediates endomembrane-dependent signaling of the BRAFV600E-MAPK pathway.
- |||||||||| Tafinlar (dabrafenib) / Novartis, Zelboraf (vemurafenib) / Roche
Antisense-oligonucleotide therapy targeting BRAF alleviates pediatric brain tumors with intractable epilepsy (Section 16; Poster Board #1) - Mar 14, 2023 - Abstract #AACR2023AACR_4990;
In our study, ASO therapy targeting BRAF shows strong therapeutic effects on various aspects of BRAF-derived pediatric brain tumors, including the epileptic seizures, tumor size, survival rate as well as dysmorphic neurons. Therefore, ASO therapy targeting BRAF will be a promising and effect therapy in BRAF-derived pediatric brain tumors with intractable epilepsy.
- |||||||||| Clinical use of next-generation sequencing panel in pediatric oncology patients (Section 44; Poster Board #8) - Mar 14, 2023 - Abstract #AACR2023AACR_4723;
Application of NGS panel in pediatric cancer aid in diagnosis, treatment decision, clinical trial enrollment and germline risk determination. Although there are not many cases linked with molecular target-based therapy, it is leading to clinical benefits in pediatric patients and more understanding genomic profiling of pediatric cancer.
- |||||||||| PHI-501 / Pharos iBT
PHI-501, a novel and potent pan-RAF inhibitor in metastatic melanoma (Section 17; Poster Board #17) - Mar 14, 2023 - Abstract #AACR2023AACR_3872;
Melanoma cells harboring BRAF non-V600/NRAS or BRAF common V600E mutations exhibited significantly reduced proliferation, increased apoptosis and inhibited migration upon treatment with PHI-501. The results of this study suggest that PHI-501 has a potential to overcome the limited response in the treatment of melanoma, and warrant evaluation of PHI-501 as a single agent to treat both BRAF-and NRAS-mutated metastatic melanoma.
- |||||||||| Journal: Current insights into the role of BRAF inhibitors in treatment of melanoma. (Pubmed Central) - Mar 9, 2023
Sorafenib, Vemurafenib, Dabrafenib, and Encorafenib are FDA-approved for the treatment of BRAF. Understanding melanoma pathogenesis, RAS/RAF/MEK/ERK or MAPK pathway, and BRAF conformations, mutations, the problems with FDA approved BRAF inhibitors will be important for new drug discovery, modification of existing BRAF barriers to improve target specific action, and prevent increasing response levels while minimizing toxicity.
- |||||||||| Zelboraf (vemurafenib) / Roche
Sestrin2 contributes to BRAF inhibitor resistance via reducing redox vulnerability of melanoma cells () - Mar 4, 2023 - Abstract #ISID2023ISID_1453;
Our findings demonstrated the contribution of Sestrin2 to the development of BRAFi resistance and the fact that the combination of mTOR blocker assisted Sestrein2 ablation in eliminating BRAFi resistance of melanoma. Therefore, mTOR and Sestrin2 may be novel combinatorial therapeutic targets to overcome BRAFi resistance of melanoma.
- |||||||||| Zelboraf (vemurafenib) / Roche
Quiescent melanoma cells represent increased adhesive capacities () - Mar 4, 2023 - Abstract #ISID2023ISID_1441;
Our study revealed that both dacarbazine or BRAF V600E inhibitor vemurafenib treatment of melanoma cells in vitro induced not only apoptosis but a transition of proliferative cells in G0 phase of a cell cycle. Further expression analysis of
- |||||||||| Cotellic (cobimetinib) / Exelixis, Roche, Zelboraf (vemurafenib) / Roche
Melatonin enhances BRAF/MEK inhibitors-induced disturbances in mitochondrial homeostasis and oncogenic pathways in human melanoma () - Mar 4, 2023 - Abstract #ISID2023ISID_1400;
In addition, we also found that the combined treatment caused significant mechanistic changes in cellular bioenergetics by (i) uncoupling of oxidative phosphorylation (OXPHOS), (ii) attenuation of glycolysis (Seahorse assessment), (iii) dissipation of mitochondrial transmembrane potential (mt??) (FACS), and (iv) changes in mitochondrial morphology (TEM). Our results extend previously published data and they provide new perspectives and evidence for introduction of melatonin as an add-on complementary therapy in future treatment of melanoma-affected patients.
- |||||||||| Zelboraf (vemurafenib) / Roche
Drug-induced phototoxicity: Disruption of 6-formylindolo[3,2-b]carbazole metabolism sensitizes keratinocytes to UVA-induced apoptosis () - Mar 4, 2023 - Abstract #ISID2023ISID_1395;
Recently, we reported that a FICZ accumulation and the associated sensitization towards UVA radiation may contribute to the phototoxicity of the BRAF inhibitor vemurafenib...We identified the EGFR inhibitor erlotinib and the immunosuppressant leflunomide to sensitize keratinocytes to FICZ/UVA-induced phototoxicity by inhibiting CYP1A1 activity...Notably, only one compound sensitized to UVA-induced apoptosis in the absence of FICZ. In summary, our data emphasize that drug-induced phototoxicity often underlies an indirect mechanism, i.e. a disturbance of the metabolism of endogenous photosensitizers, such as FICZ, a finding which should be considered during drug development.
- |||||||||| Rybrevant (amivantamab-vmjw) / Genmab, J&J
Amivantamab-induced pityriasis amiantacea () - Mar 4, 2023 - Abstract #ISID2023ISID_1319;
The scalp was then treated with fluocinolone 0.01% oil for one week, followed by alternating ketoconazole 2% and pyrithione zinc 1% shampoos...Cutis. 2019 Jan;103(1):46-50.
- |||||||||| Braftovi (encorafenib) / Ono Pharma, Pierre Fabre, Pfizer, Mektovi (binimetinib) / Ono Pharma, Pierre Fabre, Pfizer
Enrollment closed, Trial completion date, Trial primary completion date, HEOR, Metastases: OCEANMIST: Comparative Effectiveness of Targeted Therapies in BRAF Positive Metastatic Melanoma in the US (clinicaltrials.gov) - Mar 2, 2023
P=N/A, N=1, Active, not recruiting,
2019 Jan;103(1):46-50. Recruiting --> Active, not recruiting | Trial completion date: Jan 2023 --> Jul 2024 | Trial primary completion date: Jan 2023 --> Jul 2024
- |||||||||| Zelboraf (vemurafenib) / Roche
Journal: Efficient prioritization of CRISPR screen hits by accounting for targeting efficiency of guide RNA. (Pubmed Central) - Feb 28, 2023
We identified the variations in target cleavage efficiency, even in optimized sgRNA libraries, that pose a strong bias in phenotype and developed an analysis method that corrects phenotype score by the measured differences in the targeting efficiency among sgRNAs. Collectively, we expect that our new analysis method will more accurately identify genes that confer the phenotype of interest.
- |||||||||| Zelboraf (vemurafenib) / Roche
Journal: Cooperative induction of receptor tyrosine kinases contributes to adaptive MAPK drug resistance in melanoma through the PI3K pathway. (Pubmed Central) - Feb 27, 2023
We find that melanoma cell lines characterized as proliferative (high MITF low AXL), transform into an invasive (low MITF, high AXL) cell state after vemurafenib resistance, indicating novel feedback loops and advanced compensatory regulation mechanisms between the master regulators, receptors, and ligands involved in vemurafenib-induced resistance. Together, our data disclose fine-tuned mechanisms involved in RTK-facilitated vemurafenib resistance that will be challenging to overcome by using single drug targeting strategies against melanoma.
- |||||||||| Erbitux (cetuximab) / Eli Lilly, Zelboraf (vemurafenib) / Roche
Trial completion, Combination therapy, Metastases: VIC-BRAFMT-mCRC: Efficacy of VIC Regimen in BRAF Mutant Metastatic Colorectal Cancer (clinicaltrials.gov) - Feb 15, 2023
P1/2, N=37, Completed,
Together, our data disclose fine-tuned mechanisms involved in RTK-facilitated vemurafenib resistance that will be challenging to overcome by using single drug targeting strategies against melanoma. Recruiting --> Completed
- |||||||||| Tafinlar (dabrafenib) / Novartis, Zelboraf (vemurafenib) / Roche
Journal: Vemurafenib and Dabrafenib Downregulates RIPK4 Level. (Pubmed Central) - Feb 12, 2023
However, the silencing of RIPK4 did not induce apoptosis or necroptosis. Our study suggests that RIPK4 may be an off-target for BRAF inhibitors.
- |||||||||| Mifeprex (mifepristone) / Danco Laboratories, Zelboraf (vemurafenib) / Roche
Review, Journal, IO biomarker, Metastases: Survival Mechanisms of Metastatic Melanoma Cells: The Link between Glucocorticoids and the Nrf2-Dependent Antioxidant Defense System. (Pubmed Central) - Feb 12, 2023
Recent studies revealed that VMF/PLX40-32 (vemurafenib, a selective inhibitor of mutant BRAF) increases mitochondrial respiration and reactive oxygen species (ROS) production in BRAF human melanoma cell lines...Thus, it is likely that a glucocorticoid receptor antagonist (RU486) could increase the efficacy of BRAF-related therapy in BRAF-mutated melanoma...Moreover, melanoma resistance was decreased if AKT and NF-?B signaling pathways were blocked. These findings highlight mechanisms by which metastatic melanoma cells adapt to survive and could help in the development of most effective therapeutic strategies.
- |||||||||| Zelboraf (vemurafenib) / Roche
Journal: Resistance to BRAF Inhibitors: EZH2 and Its Downstream Targets as Potential Therapeutic Options in Melanoma. (Pubmed Central) - Feb 12, 2023
Therefore, we wondered whether inhibition of EZH2 would be a way to overcome resistance to vemurafenib...When we inhibited both BRAF and PLK1, we achieved an improved response of BRAFi-resistant melanoma cells, which was comparable to the combined inhibition of BRAF and EZH2. These results thus reveal that targeting EZH2 or its downstream targets, such as PLK1, in combination with BRAF inhibitors are potential novel therapeutic options in melanomas with BRAF mutations.
- |||||||||| Gazyva (obinutuzumab) / Roche, Biogen, Zelboraf (vemurafenib) / Roche
Trial completion date, Trial primary completion date: A Phase II Study of the BRAF Inhibitor, Vemurafenib, Plus Obinutuzumab in Patients With Previously Untreated Classical Hairy Cell Leukemia (clinicaltrials.gov) - Feb 8, 2023
P2, N=30, Active, not recruiting,
No abstract available Trial completion date: Jan 2023 --> Jan 2024 | Trial primary completion date: Jan 2023 --> Jan 2024
- |||||||||| Zelboraf (vemurafenib) / Roche
Erdheim-Chester disease - A rare multisystem disorder () - Feb 4, 2023 - Abstract #BSR2023BSR_380;
This patient had skeletal, cardiac, lung, and gastrointestinal involvement resulting in his dyspnoea and weight loss. Initial treatment involves corticosteroid and interferon.
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