Biology subjects

Dibus, N.

Publications and source records attributed to Dibus, N..

5 recordsLinked to original sources

bioRxiv2025

Pharmacokinetics and efficacy of tank-water administered BRAF-inhibitor dabrafenib in a zebrafish model of BRAF-mutant melanoma

Zebrafish models are widely used to study the biology of BRAF-mutant melanoma. However, long-term treatment of adult fish with small molecule BRAF inhibitors is challenging, limiting the usefulness of this model to study treatment-induced effects in melanoma biology. In addition, pharmacokinetic studies on small molecule inhibitors in zebrafish that could inform rational dosing strategies, are largely lacking. Here, we have assessed the pharmacokinetics, metabolism and efficacy of continuous tank water -administered BRAF-inhibitor dabrafenib in adult zebrafish. Our results demonstrate that dabrafenib is quickly absorbed from the tank water, reaching efficacious plasma levels within one hour following treatment, but also shows fast elimination kinetics with a half-life of 1.6 hours. We could detect most of the human metabolites of dabrafenib in zebrafish, suggesting that dabrafenib metabolism in zebrafish follows a similar process as in humans. Continuous tank water -administered dabrafenib led to therapeutically relevant steady-state plasma levels that inhibited the BRAF-driven signaling and growth in zebrafish melanoma cells in vitro, and resulted in robust in vivo efficacy in a genetic zebrafish model of BRAF-mutant melanoma, with no apparent toxicity. Together, our results demonstrate that continuous tank water -administered dabrafenib provides a feasible, efficient, and well-tolerated dosing strategy to study treatment-related effects in zebrafish models of BRAF-mutant melanoma. We expect that tank water-administration may also facilitate the dosing of other small molecule inhibitors, especially those with short in vivo half-life in zebrafish. HighlightsO_LIPharmacokinetic analysis demonstrates fast absorption kinetics and short plasma half-life for tank water -administered dabrafenib in zebrafish C_LIO_LIDabrafenib is metabolized in zebrafish following a similar metabolic process as in humans C_LIO_LITank water -administered dabrafenib provides a feasible, efficient, and well-tolerated dosing strategy to study treatment-related effects in zebrafish models of BRAF-mutant melanoma C_LIO_LITank water-administration may facilitate dosing of small molecule inhibitors with short in vivo half-life in zebrafish C_LI

cancer biology↗

bioRxiv2024

Recurrent cancer-associated ERBB4 mutations are transforming and confer resistance to targeted therapies

Receptor tyrosine kinase ERBB4 (HER4) is frequently mutated in human cancer, and ERBB4 mutations have been identified in patients relapsing on targeted therapy. Here, we addressed the functional consequences of recurrent cancer-associated ERBB4 mutations that are located at regions important for dimer interactions and/or are paralogous to known oncogenic hotspot mutations in other ERBB genes. Eleven out of 18 analyzed mutations were transforming in cell models, thus suggesting oncogenic potential for more than half of the recurrent ERBB4 mutations. More detailed analyses of the most potent mutations, S303F, E452K and L798R, showed that they are activating, can co-operate with other ERBB receptors and are targetable with clinically available second-generation pan-ERBB inhibitors neratinib, afatinib and dacomitinib. Furthermore, the S303F mutation, together with a previously identified activating ERBB4 mutation, E715K, promoted resistance to third-generation EGFR inhibitor osimertinib in EGFR-mutant lung cancer model in vitro and in vivo. Together, these results are expected to facilitate clinical interpretation of the most recurrent cancer-associated ERBB4 mutations. The findings provide rationale for testing the efficacy of clinically used pan-ERBB inhibitors in patients harboring driver ERBB4 mutations both in the treatment-naive setting, and upon development of resistance to targeted agents.

cancer biology↗

bioRxiv2024

CRL4DCAF12 regulation of MCMBP ensures optimal licensing of DNA replication

The minichromosome maintenance (MCM2-7) protein complexes are central drivers of genome duplication. Distinct protein pools, parental and nascent MCMs, and their precise equilibrium are essential to sustain error-free DNA replication1. However, the mechanism responsible for generating these pools and maintaining their equilibrium remains largely unexplored. Here, we identified CRL4DCAF12 as a new factor controlling the assembly of nascent MCM complexes. During MCM biogenesis, MCMBP facilitates the assembly and transport of newly synthesized MCM3-7 subcomplexes into the nucleus2,3. Once in the nucleus, the MCM2 subunit must be incorporated into the MCM3-7 subcomplex, while MCMBP needs to be removed. CRL4DCAF12 facilitates the degradation of MCMBP and thereby regulates the assembly of MCM2-7 complexes. The absence of CRL4DCAF12 adversely affects the level of chromatin-bound nascent MCMs, resulting in accelerated replication forks and genome instability. Collectively, our findings uncovered the molecular mechanism underlying nascent MCM production essential to counteract genome instability and tumor formation.

cell biology↗

bioRxiv2023

Matters Arising: FBXO38 does not control PD-1 stability

SKP1-CUL1-F-box protein (SCF) ubiquitin ligases are versatile protein complexes that mediate the ubiquitination of substrates, which are recognized by their F-box-domain- containing subunits1. One of these substrate receptors is FBXO38. Its gene has been found to be mutated in several families with early-onset distal hereditary motor neuronopathy2. SCFFBXO38 ubiquitin ligase controls the stability of ZXDB, a nuclear factor associated with the centromeric chromatin protein CENP-B3. Moreover, the loss of FBXO38 results in growth retardation and defect in spermatogenesis characterized by deregulation of the Sertoli cell transcription program and centromere integrity4. A report by Meng et al. proposed that SCFFBXO38 regulates the protein levels of the PD-1 inhibitory receptor (also known as CD279, PDCD1) in T cells5. Here, we have re-addressed the conclusions by Meng et al. using Fbxo38KO/KO mice and cell systems. We have found no evidence indicating that FBXO38 controls the abundance and stability of PD-1.

cell biology↗

bioRxiv2022

Tumor suppressor Hypermethylated in Cancer 1 represses expression of cell cycle regulator E2F7 in human primary cells

Hypermethylated in Cancer 1 (HIC1) is an established tumor suppressor, which is frequently inactivated in various cancers. In colorectal carcinoma (CRC), silencing of HIC1 has been recognized as one of the important events in malignant tumor progression. Strikingly, CRC patients with high HIC1 expression have a worse prognosis than patients with relatively low HIC1 mRNA levels. To analyze the function of HIC1, we performed expression profiling of human primary fibroblasts after downregulation of HIC1 by RNA interference. We show that HIC1 deficiency triggers a p53-dependent response and that disruption of the HIC1 gene in human colon cells delays cell cycle progression under serum deficiency conditions. Moreover, treatment with etoposide, a DNA-damaging agent, significantly impairs the proliferation rate and dynamics of damaged DNA repair in HIC1-deficient compared with wild-type cells. One of the genes upregulated in HIC1-depleted cells encodes cell cycle regulator E2F7. E2F7 is an atypical member of the E2F family, which functions primarily as a transcriptional repressor, and its downregulation is essential for proper cell cycle progression and expression of genes involved in DNA repair. We demonstrated that E2F7 is indeed the target of transcriptional repression mediated by HIC1. Moreover, our results suggest that the phenotypic manifestations associated with loss of the HIC1 gene, in particular the changes in cell cycle progression and slowed repair of damaged DNA, are caused by dysregulation of E2F7 expression. Finally, we observed an inverse relationship between HIC1 and E2F7 in a panel of CRC. Importantly, CRC patients who express relatively high levels of E2F7 have a remarkably better prognosis than patients with intermediate or low levels of E2F7 expression.

cancer biology↗