Regulation of TORC1 by MAPK Signaling Determines Sensitivity and Acquired Resistance to Trametinib in Pediatric <i>BRAFV600E</i> Brain Tumor Models

Li, Fuyang; Bondra, Kathryn; Ghilu, Samson; Studebaker, Adam; Liu, Qianqian; Michalek, Joel E.; Kogiso, Mari; Li, Xiao-Nan; Kalapurakal, John A.; James, C. David; Burma, Sandeep; Kurmasheva, Raushan T.; Houghton, Peter J.

doi:10.1158/1078-0432.ccr-22-1052

Cited by 3 publications

(3 citation statements)

References 57 publications

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“…They found that the decoupling of TORC1 signaling, originally a downstream pathway of MEK, led to resistance to trametinib; moreover, the combination of a TORC1 inhibitor and trametinib postponed the development of trametinib resistance. 188 …”

Section: Pdx Model In Targeted Therapy Researchmentioning

confidence: 99%

Patient-derived xenograft models in cancer therapy: technologies and applications

Liu

Cai

et al. 2023

Sig Transduct Target Ther

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Patient-derived xenograft (PDX) models, in which tumor tissues from patients are implanted into immunocompromised or humanized mice, have shown superiority in recapitulating the characteristics of cancer, such as the spatial structure of cancer and the intratumor heterogeneity of cancer. Moreover, PDX models retain the genomic features of patients across different stages, subtypes, and diversified treatment backgrounds. Optimized PDX engraftment procedures and modern technologies such as multi-omics and deep learning have enabled a more comprehensive depiction of the PDX molecular landscape and boosted the utilization of PDX models. These irreplaceable advantages make PDX models an ideal choice in cancer treatment studies, such as preclinical trials of novel drugs, validating novel drug combinations, screening drug-sensitive patients, and exploring drug resistance mechanisms. In this review, we gave an overview of the history of PDX models and the process of PDX model establishment. Subsequently, the review presents the strengths and weaknesses of PDX models and highlights the integration of novel technologies in PDX model research. Finally, we delineated the broad application of PDX models in chemotherapy, targeted therapy, immunotherapy, and other novel therapies.

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Section: Pdx Model In Targeted Therapy Researchmentioning

confidence: 99%

Patient-derived xenograft models in cancer therapy: technologies and applications

Liu

Cai

et al. 2023

Sig Transduct Target Ther

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“…The PDX-to-cell line approach was used to generate a heterozygous BRAF V600E -mutated cell line BT-40 ( 63 ). BT-40 cells exhibited sensitivity to MAPK inhibitors selumetinib and trametinib ( 64 , 105 ). A MAPK inhibitor library screen against BT-40 expressing a luciferase-based MAPK reporter assay revealed distinct sensitivities to single inhibitors, including next-generation RAF inhibitors, and synergistic effects of different inhibitor classes ( 106 ).…”

Section: In Vitro Modeling and Drug Strategiesmentioning

confidence: 99%

“…BRAF missense mutations have been identified in these PDX by molecular profiling, but due to the relative scarcity of BRAF V600E altered CNS tumors amongst brain tumor patients, PDX for these tumors are rare. A PDX biobank specifically focused on BRAF V600E -mutated gliomas is currently lacking due to the scarcity of patient material, and the difficulty in retrieving complete patients’ clinical data, pathologies, gene expression profiles, and drug responsiveness ( 64 ). However, there is great potential for this to be an authoritative resource for developing new treatments and personalized medicine approaches.…”

Section: In Vivo Modelingmentioning

confidence: 99%

Successes and challenges in modeling heterogeneous BRAFV600E mutated central nervous system neoplasms

Xing,

Panovska,

Petritsch

2023

Front. Oncol.

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Central nervous system (CNS) neoplasms are difficult to treat due to their sensitive location. Over the past two decades, the availability of patient tumor materials facilitated large scale genomic and epigenomic profiling studies, which have resulted in detailed insights into the molecular underpinnings of CNS tumorigenesis. Based on results from these studies, CNS tumors have high molecular and cellular intra-tumoral and inter-tumoral heterogeneity. CNS cancer models have yet to reflect the broad diversity of CNS tumors and patients and the lack of such faithful cancer models represents a major bottleneck to urgently needed innovations in CNS cancer treatment. Pediatric cancer model development is lagging behind adult tumor model development, which is why we focus this review on CNS tumors mutated for BRAFV600E which are more prevalent in the pediatric patient population. BRAFV600E-mutated CNS tumors exhibit high inter-tumoral heterogeneity, encompassing clinically and histopathological diverse tumor types. Moreover, BRAFV600E is the second most common alteration in pediatric low-grade CNS tumors, and low-grade tumors are notoriously difficult to recapitulate in vitro and in vivo. Although the mutation predominates in low-grade CNS tumors, when combined with other mutations, most commonly CDKN2A deletion, BRAFV600E-mutated CNS tumors are prone to develop high-grade features, and therefore BRAFV600E-mutated CNS are a paradigm for tumor progression. Here, we describe existing in vitro and in vivo models of BRAFV600E-mutated CNS tumors, including patient-derived cell lines, patient-derived xenografts, syngeneic models, and genetically engineered mouse models, along with their advantages and shortcomings. We discuss which research gaps each model might be best suited to answer, and identify those areas in model development that need to be strengthened further. We highlight areas of potential research focus that will lead to the heightened predictive capacity of preclinical studies, allow for appropriate validation, and ultimately improve the success of “bench to bedside” translational research.

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3‐methyl‐1H‐indol‐1‐yl dimethylcarbamodithioate attenuates periodontitis through targeting MAPK signaling pathway‐regulated mitochondrial function

Jiang,

Ren,

Mao

et al. 2024

J of Periodontal Research

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Periodontitis, the second most common oral disease, is primarily initiated by inflammatory responses and osteoclast differentiation, in which the MAPK signaling pathway and mitochondrial function play important roles. 3‐methyl‐1H‐indol‐1‐yl dimethylcarbamodithioate (3o), a hybrid of indole and dithiocarbamate, was first synthesized by our group. It has shown anti‐inflammatory activity against lipopolysaccharide‐induced acute lung injury. However, it is not known if 3o can exert effects in periodontitis. In vitro study: LPS‐induced macrophage inflammation initiation and a receptor activator of nuclear factor κB ligand‐stimulated osteoclast differentiation model were established. Cell viability, inflammatory cytokines, osteoclast differentiation, the MAPK signaling pathway, and mitochondrial function before and after treatment with 3o were investigated. In vivo study: Alveolar bone resorption, inflammatory cytokine expression, osteoclast differentiation, and the underlying mechanisms were assessed in mice with periodontitis. Inflammatory cytokine expression and osteoclast differentiation appeared downregulated after 3o treatment. 3o inhibited the MAPK signaling pathway and restored mitochondrial function, including mitochondrial reactive oxygen species, mitochondrial membrane potential, and ATP production. Meanwhile, 3o reduced inflammation activation and bone resorption in mice with periodontitis, reflected by the decreased expression of inflammatory cytokines and osteoclasts, implying that 3o inhibited the MAPK signaling pathway and the mitochondrial oxidative DNA damage marker 8‐OHdG. These results highlight the protective role of 3o in periodontitis in mice and reveal an important strategy for preventing periodontitis.

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Regulation of TORC1 by MAPK Signaling Determines Sensitivity and Acquired Resistance to Trametinib in Pediatric BRAFV600E Brain Tumor Models

Cited by 3 publications

References 57 publications

Patient-derived xenograft models in cancer therapy: technologies and applications

Patient-derived xenograft models in cancer therapy: technologies and applications

Successes and challenges in modeling heterogeneous BRAFV600E mutated central nervous system neoplasms

3‐methyl‐1H‐indol‐1‐yl dimethylcarbamodithioate attenuates periodontitis through targeting MAPK signaling pathway‐regulated mitochondrial function

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