Dabrafenib is a BRAF inhibitor that has been demonstrated to be efficacious in the treatment of melanoma and non-small-cell lung cancer patients with BRAF V600E mutations. The objective of this study was to investigate the effects of 51 traditional Chinese medicines on the metabolism of dabrafenib and to further investigate the inhibitory effect of imperatorin. The quantification of dabrafenib and its metabolite hydroxy-dabrafenib was carried out using a sensitive, rapid, and accurate assay method based on ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The results of in vitro experiments showed that 20 drugs inhibited the metabolism of dabrafenib by more than 80 %. In a further study of imperatorin on dabrafenib, the half-maximal inhibitory concentration (IC50) values of imperatorin on dabrafenib were 0.22 μM and 3.68 μM in rat liver microsomes (RLM) and human liver microsomes (HLM), respectively, while the inhibition mechanisms were non-competitive and mixed type inhibition, respectively. The results of in vivo experiments demonstrated that in the presence of imperatorin, the AUC(0-t), AUC(0-∞), Cmax, and Tmax of dabrafenib were increased by 2.38-, 2.26-, 1.05-, and 6.10-fold, respectively, while CLz/F was decreased by 67.9 %. In addition, Tmax of hydroxy-dabrafenib was increased by 1.4-fold. The results of the research showed that imperatorin had a consistent inhibitory effect on dabrafenib in vitro and in vivo. When the concurrent use of dabrafenib and imperatorin is unavoidable, clinicians should closely monitor for potential adverse events and make timely adjustments to the administered dosage.

Lenvatinib is a multi-target inhibitor that exerts anti-tumor effects by inhibiting angiogenesis and is now commonly used as a first-line treatment for hepatocellular carcinoma. However, with the widespread use of lenvatinib, the problem of serious and fatal hepatotoxicity has become increasingly prominent. Currently, the mechanism behind this toxicity is not yet understood, and as a result, there is a lack of safe and effective intervention strategies with minimal side effects. Here, we established the model of lenvatinib-induced liver injury in vivo and in vitro and found that lenvatinib caused hepatotoxicity by inducing apoptosis. Further mechanistic studies in cellular models revealed that lenvatinib upregulated death receptor signaling pathway, which activated the downstream effector Caspase-8, and ultimately led to apoptosis. Meanwhile, lenvatinib-induced apoptosis was associated with ROS generation and DNA damage. In addition, after screening marketed drugs and natural products in combination with cellular modeling, we identified a potential co-administered drug, dabrafenib, which could alleviate lenvatinib-induced hepatotoxicity. Further mechanistic studies revealed that dabrafenib attenuated lenvatinib-induced hepatotoxicity by inhibiting the activation of the death receptor signaling pathway. Subsequently, cancer cell proliferation assays confirmed that dabrafenib did not antagonize the antitumor effects of lenvatinib. In conclusion, our results validate that apoptosis caused by the death receptor signaling pathway is the key cause of lenvatinib-induced hepatotoxicity, and dabrafenib alleviates lenvatinib-induced hepatotoxicity by inhibiting this pathway.

The v-raf murine sarcoma viral oncogenic homolog B1 (BRAF) V600E is a rare mutation that functions as an oncogenic driver in patients with non-small cell lung cancer (NSCLC) leading to the overactivation of the RAS-RAF-MEK-ERK (MAPK) pathway and the subsequent uncontrolled cell proliferation. Understanding the mechanism behind BRAF mutation, its inhibition, and relationship to the upstream and downstream effector is essential for advancing treatment strategies for NSCLC patients with the BRAF V600E mutation. Next-generation sequencing studies have identified the presence of breast cancer susceptibility gene 1/2 (BRCA1/2) mutations in NSCLC patients, which are pathogenic variants associated with breast, ovarian, and prostate cancers. Although poly ADP-ribose polymerase (PARP) inhibitors are currently an approved treatment option for malignant tumors linked to BRCA1/2 pathogenic variants, the therapeutic potential of PARP inhibitors in NSCLC remains unclear. The development of genetic testing provides a platform for investigating the pathophysiological mechanisms of genetic mutations above. Here, we report a novel case of a middle-aged non-smoking female diagnosed with BRAF V600E and BRCA2 germline mutated lung adenocarcinoma, who had previously undergone a diverse array of cancer-targeted therapies, including PARP inhibitor, before the identification of the BRAF V600E mutation. Following this, a combination of dabrafenib and trametinib was administered and induced a rapid and positive response within two months. Our case not only highlights the importance of dynamic and repetitive genetic testing in managing patients, but contributes to the growing body of clinical evidence supporting the efficacy of BRAF/MEK co-inhibition in patients harboring a BRAF V600E mutation and provokes thinking for further research into the impact of PARP inhibitors in BRCA1/2-mutated NSCLC.

Multiple sclerosis is an autoimmune disease that causes inflammatory damage to the central nervous system. At present, the pathogenesis of the disease is unknown. There is a lack of few effective therapy medications available. Therefore, it is necessary to further explore the pathogenesis of this illness and develop potential therapeutic drugs. Dabrafenib is potential therapeutic medicine for nervous system disease. In this study, we preliminarily studied the possible mechanism of dabrafenib in the treatment of multiple sclerosis from the perspective of ferroptosis. First, we observed that dabrafenib significantly improved symptoms of gait abnormalities, limb weakness or paralysis, and down-regulated levels of spinal cord inflammation in an experimental autoimmune encephalitis (EAE) model. Meanwhile, we also observed that dabrafenib could inhibit the proteins of ferroptosis in spinal cord tissue of EAE mice by Western blot. The results of immunohistochemical analysis showed that the effect of dabrafenib on ferroptosis mainly occurred in microglia. Second, dabrafenib was demonstrated to be able to inhibit the S phase of the cell cycle, reduce ROS levels, and reinstate mitochondrial activity in the LPS-induced BV2 inflammatory cell model. Futhermore, we found that dabrafenib inhibits P-JAK2 and P-STAT3 activation by acting Axl receptor, which in turn prevents neurogenic inflammation in microglia. The co-stimulated BV2 cell model with LPS and Erastin also verified these findings. Ultimately, the Axl knockout mice used to construct the EAE model allowed for the confirmation that dabrafenib prevented ferroptosis in microglia by up-regulating Axl receptor, which reduced the inflammatory demyelination associated with EAE. In summary, our research demonstrates the advantages of dabrafenib in multiple sclerosis treatment, which can prevent ferroptosis in microglia in multiple sclerosis through up-regulating Axl receptor, thus halting the progression of multiple sclerosis.

Decabromodiphenyl ether (BDE209) has been demonstrated to be associated with thyroid dysfunction and thyroid carcinoma risk as a widely used brominated flame retardants. Although dabrafenib has been confirmed to be a promising therapeutic agent for papillary thyroid carcinoma (PTC) harboring BRAFV600E mutation, the rapid acquired dabrafenib resistance has brought a great challenge to clinical improvement and the underpinning mechanisms remain poorly defined. By treating PTC-derived and normal follicular epithelial cell lines with BDE209, we assessed its impact on the MAPK pathway\'s activation and evaluated the resultant effects on cell viability and signaling pathways, utilizing methods such as Western blot, IF staining, and RNA-seq bioinformatic analysis. Our findings reveal that BDE209 exacerbates MAPK activation, undermining dabrafenib\'s inhibitory effects by triggering the EGFR pathway, thereby highlighting BDE209\'s potential to diminish the pharmacological efficacy of dabrafenib in treating BRAF-mutated PTC. This research underscores the importance of considering environmental factors like BDE209 exposure in the effective management of thyroid carcinoma treatment strategies.

Monocyte-derived tumor-associated macrophages (Mo-TAMs) intensively infiltrate diffuse gliomas with remarkable heterogeneity. Using single-cell transcriptomics, we chart a spatially resolved transcriptional landscape of Mo-TAMs across 51 patients with isocitrate dehydrogenase (IDH)-wild-type glioblastomas or IDH-mutant gliomas. We characterize a Mo-TAM subset that is localized to the peri-necrotic niche and skewed by hypoxic niche cues to acquire a hypoxia response signature. Hypoxia-TAM destabilizes endothelial adherens junctions by activating adrenomedullin paracrine signaling, thereby stimulating a hyperpermeable neovasculature that hampers drug delivery in glioblastoma xenografts. Accordingly, genetic ablation or pharmacological blockade of adrenomedullin produced by Hypoxia-TAM restores vascular integrity, improves intratumoral concentration of the anti-tumor agent dabrafenib, and achieves combinatorial therapeutic benefits. Increased proportion of Hypoxia-TAM or adrenomedullin expression is predictive of tumor vessel hyperpermeability and a worse prognosis of glioblastoma. Our findings highlight Mo-TAM diversity and spatial niche-steered Mo-TAM reprogramming in diffuse gliomas and indicate potential therapeutics targeting Hypoxia-TAM to normalize tumor vasculature.

BACKGROUND: Melanoma is the most lethal skin cancer characterized by its high metastatic potential. In the past decade, targeted and immunotherapy have brought revolutionary survival benefits to patients with advanced and metastatic melanoma, but these treatment responses are also heterogeneous and/or do not achieve durable responses. Therefore, novel therapeutic strategies for improving outcomes remain an unmet clinical need. The aim of this study was to evaluate the therapeutic potential and underlying molecular mechanisms of RC48, a novel HER2-target antibody drug conjugate, either alone or in combination with dabrafenib, a V600-mutant BRAF inhibitor, for the treatment of advanced BRAF-mutant cutaneous melanoma.
METHODS: We evaluated the therapeutic efficacy of RC48, alone or in combination with dabrafenib, in BRAF-mutant cutaneous melanoma cell lines and cell-derived xenograft (CDX) models. We also conducted signaling pathways analysis and global mRNA sequencing to explore mechanisms underlying the synergistic effect of the combination therapy.
RESULTS: Our results revealed the expression of membrane-localized HER2 in melanoma cells. RC48 effectively targeted and inhibited the growth of HER2-positive human melanoma cell lines and corresponding CDX models. When used RC48 and dabrafenib synergically induced tumor regression together in human BRAF-mutant melanoma cell lines and CDX models. Mechanically, our results demonstrated that the combination therapy induced apoptosis and cell cycle arrest while suppressing cell motility in vitro. Furthermore, global RNA sequencing analysis demonstrated that the combination treatment led to the downregulation of several key signaling pathways, including the PI3K-AKT pathway, MAPK pathway, AMPK pathway, and FOXO pathway.
CONCLUSIONS: These findings establish a preclinical foundation for the combined use of an anti-HER2 drug conjugate and a BRAF inhibitor in the treatment of BRAF-mutant cutaneous melanoma.

UNASSIGNED: BRAF is a pivotal driver gene in cancer development. Based on this, the combination of dabrafenib and trametinib was approved for treating NSCLC patients with BRAFV600E mutations. However, the majority of BRAF mutations in lung cancer are non-V600E variants, particularly class III mutants, which currently lack targeted therapeutic options and result in unfavorable clinical outcomes.
UNASSIGNED: We present a case of advanced lung adenocarcinoma with a class III BRAFG466V mutation. The patient experienced significant pleural and pericardial effusion, leading to chest tightness and an inability to lie flat. Severe pain and limited mobility from lumbar destruction seriously affected the patient\'s quality of life. Due to the patient\'s intolerance to chemotherapy, dabrafenib and trametinib combination therapy was chosen. After three months of targeted therapy, the patient\'s overall condition significantly improved, enabling self-care, and achieving partial response (PR) as an indicator of treatment efficacy.
UNASSIGNED: The combination therapy of dabrafenib and trametinib demonstrates remarkable clinical benefits for lung adenocarcinoma patients with the BRAFG466V mutation. Targeted therapy should be considered for patients with BRAF class III mutations, especially those in poor general condition and may not tolerate chemotherapy.

UNASSIGNED: The pulmonary sarcomatoid carcinoma (PSC) is a rare and aggressive subtype of NSCLC with rapid progression and poor prognosis, and is resistant to conventional chemotherapy. Most PSC cases have potential targetable genomic alterations. Approximately 7% of PSC patients have BRAF mutations, and the efficacy of dabrafenib and trametinib in BRAFV600E mutated PSC is unclear.
UNASSIGNED: Our report describes a patient with mutated BRAFV600E PSC who underwent surgery and adjuvant chemotherapy early but quickly relapsed. Both chemotherapy and immunotherapy were ineffective for him, combined dabrafenib and trametinib produced a 6-month progression-free survival, and a partial response was observed in the tumor response evaluation. As a result of financial pressure, he stopped taking the targeted drugs, and his disease rapidly progressed.
UNASSIGNED: Dabrafenib combined with trametinib provides partial remission in patients with advanced PSC with BRAFV600E mutations, and large-scale NGS panels could offer more options for PSC treatment.

Rationale: Although surgery, radioiodine therapy, and thyroid hormone therapy are the primary clinical treatments for differentiated thyroid carcinoma (DTC), effective therapy for locally advanced or progressive DTC remains challenging. BRAF V600E, the most common BRAF mutation subtype, is highly related to DTC. Previous studies prove that combination of kinase inhibitors and chemotherapeutic drugs may be a potential approach for DTC treatment. In this study, a supramolecular peptide nanofiber (SPNs) co-loaded with dabrafenib (Da) and doxorubicin (Dox) was constructed for targeted and synergistic therapy with BRAF V600E+ DTC. Methods: A self-assembling peptide nanofiber (Biotin-GDFDFDYGRGD, termed SPNs) bearing biotin at the N-terminus and a cancer-targeting ligand RGD at the C-terminus was used as a carrier for co-loading Da and Dox. D-phenylalanine and D-tyrosine (DFDFDY) are used to improve the stability of peptides in vivo. Under multiple non-covalent interactions, SPNs/Da/Dox assembled into longer and denser nanofibers. RGD ligand endows self-assembled nanofibers with targeting cancer cells and co-delivery, thereby improving cellular uptake of payloads. Results: Both Da and Dox indicated decreased IC50 values upon encapsulation in SPNs. Co-delivery of Da and Dox by SPNs exhibited the strongest therapeutic effect in vitro and in vivo by inhibiting ERK phosphorylation in BRAF V600E mutant thyroid cancer cells. Moreover, SPNs enable efficient drug delivery and lower Dox dosage, thereby significantly reducing its side effects. Conclusion: This study proposes a promising paradigm for the synergistic treatment of DTC with Da and Dox using supramolecular self-assembled peptides as carriers.