ArticleClinical cancer research : an official journal of the American Association for Cancer Research2022
Regulation of TORC1 by MAPK Signaling Determines Sensitivity and Acquired Resistance to Trametinib in Pediatric BRAFV600E Brain Tumor Models.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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7 citing papers in PubMed, 9 citations in OpenAlex.
- Efficacy Study of Vemurafenib in Children With Recurrent or Progressive BRAFJCO precision oncology · 2026Article
- SWI/SNF complexes govern ontology-specific transcription factor function in MYC-subtype atypical teratoid rhabdoid tumor.Neuro-oncology · 2025Article
- Dual inhibition of MAPK and TORC1 signaling retards development of radiation resistance in pediatric BRAFV600E glioma models.Neuro-oncology · 2025Article
- BRAF/MEK inhibition induces cell state transitions boosting immune checkpoint sensitivity in BRAFCell reports. Medicine · 2025Article
- PDX models for functional precision oncology and discovery science.Nature reviews. Cancer · 2025Review
- Patient-derived xenograft models in cancer therapy: technologies and applications.Signal transduction and targeted therapy · 2023Review
- Successes and challenges in modeling heterogeneous BRAFFrontiers in oncology · 2023Review
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13 authors at 4 institutions in 1 country.
Funding
Abstract
purposeWe investigated why three patient-derived xenograft (PDX) childhood BRAFV600E-mutant brain tumor models are highly sensitive to trametinib. Mechanisms of acquired resistance selected in situ, and approaches to prevent resistance were also examined, which may translate to both low-grade glioma (LGG) molecular subtypes. EXPERIMENTAL
designSensitivity to trametinib [MEK inhibitor (MEKi)] alone or in combination with rapamycin (TORC1 inhibitor), was evaluated in pediatric PDX models. The effect of combined treatment of trametinib with rapamycin on development of trametinib resistance in vivo was examined. PDX tissue and tumor cells from trametinib-resistant xenografts were characterized.
resultsIn pediatric models TORC1 is activated through ERK-mediated inactivation of the tuberous sclerosis complex (TSC): consequently inhibition of MEK also suppressed TORC1 signaling. Trametinib-induced tumor regression correlated with dual inhibition of MAPK/TORC1 signaling, and decoupling TORC1 regulation from BRAF/MAPK control conferred trametinib resistance. In mice, acquired resistance to trametinib developed within three cycles of therapy in all three PDX models. Resistance to trametinib developed in situ is tumor-cell-intrinsic and the mechanism was tumor line specific. Rapamycin retarded or blocked development of resistance.
conclusionsIn these three pediatric BRAF-mutant brain tumors, TORC1 signaling is controlled by the MAPK cascade. Trametinib suppressed both MAPK/TORC1 pathways leading to tumor regression. While low-dose intermittent rapamycin to enhance inhibition of TORC1 only modestly enhanced the antitumor activity of trametinib, it prevented or retarded development of trametinib resistance, suggesting future therapeutic approaches using rapamycin analogs in combination with MEKis that may be therapeutically beneficial in both KIAA1549::BRAF- and BRAFV600E-driven gliomas.
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