رسالة جامعية
TARGETING FARNESYLATION AS A NOVEL THERAPEUTIC APPROACH IN HRAS-MUTANT RHABDOMYOSARCOMA
| العنوان: | TARGETING FARNESYLATION AS A NOVEL THERAPEUTIC APPROACH IN HRAS-MUTANT RHABDOMYOSARCOMA |
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| المؤلفون: | Obasaju, Patience |
| المساهمون: | Small, Donald, Pratilas, Christine, Ladle, Brian, Kaplan, Rosandra |
| بيانات النشر: | Johns Hopkins University USA |
| سنة النشر: | 2022 |
| المجموعة: | Johns Hopkins University, Baltimore: JScholarship |
| مصطلحات موضوعية: | RAS, rhabdomyosarcoma |
| الوصف: | Activating RAS mutations are found in a subset of fusion-negative rhabdomyosarcoma (FN-RMS), and therapeutic strategies to directly target RAS in these tumors have been investigated, without clinical success to date. A potential strategy to inhibit oncogenic RAS activity is the disruption of RAS prenylation, an obligate step for RAS membrane localization and effector pathway signaling, through inhibition of farnesyltransferase (FTase). Of the major RAS family members, HRAS is uniquely dependent on FTase for prenylation, whereas NRAS and KRAS can utilize geranylgeranyl transferase (GGTase) as a bypass prenylation mechanism. Tumors driven by oncogenic HRAS may therefore be uniquely sensitive to FTase inhibition. To investigate the mutation-specific effects of FTase inhibition in RMS we developed novel RMS preclinical models and utilized tipifarnib, a potent and selective FTase inhibitor, in in vitro and in vivo models of RMS genomically characterized for RAS mutation status. FTase inhibition reduced HRAS processing, and plasma membrane localization leading to decreased GTP-bound HRAS and decreased signaling through RAS effector pathways. In HRAS-mutant cell lines, FTase inhibition reduced two-dimensional and three-dimensional cell growth, and in vivo treatment with FTase inhibition resulted in tumor growth inhibition exclusively in HRAS-mutant RMS xenografts. We found in some tumors the effects of FTase inhibition were incomplete leading only to partial responses, and we surmised that this may be due to adaptive or acquired resistance. We therefore hypothesized that HRAS-mutated FN-RMS may be sensitive to RAS pathway inhibition with combination therapies co-targeting oncogenic HRAS along with RAS pathway intermediates. We demonstrated reduced ERK signaling, and 2D and 3D growth inhibition in response to FTase inhibition in combination with MEK inhibition (trametinib) in HRAS-mutated cell lines. Additionally, we have found that FTase and MEK inhibition induced myosin heavy chain expression in HRAS-mutated cell ... |
| نوع الوثيقة: | thesis |
| وصف الملف: | application/pdf |
| اللغة: | English |
| العلاقة: | http://jhir.library.jhu.edu/handle/1774.2/67215Test |
| الإتاحة: | http://jhir.library.jhu.edu/handle/1774.2/67215Test |
| رقم الانضمام: | edsbas.A9DFB50A |
| قاعدة البيانات: | BASE |
| الوصف غير متاح. |