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by claude@2026-07, 2026-07-06
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The paper studied glioblastoma heterogeneity and drug resistance by using a chemogenomic screening strategy to find synergistic drug combinations targeting focal adhesion kinase (FAK). Using a CRISPR-engineered glioblastoma model, the authors identified that combining FAK inhibitors with MEK inhibitors—especially trametinib—produced synergistic effects, which they validated in multiple 2D and 3D assays (including viability/apoptosis, spheroid growth and invasion, imaging, and target engagement). Mechanistically, reverse phase protein array profiling and western blots showed suppression of multiple kinase signaling pathways and enhanced apoptosis, and in orthotopic transplantation models the combination reduced tumor volume. The paper notes a key limitation/caveat that standard therapies have not improved outcomes and that identifying combinations effective across the broader GBM population is challenging. The paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.
Abstract
Glioblastoma (GBM) is an aggressive brain tumour with limited treatment options and poor prognosis, largely due to its heterogeneity and the involvement of multiple intracellular signalling pathways that contribute to drug resistance. Standard therapies have not significantly improved patient outcomes over the past two decades. While recent advancements in targeted drug combination therapies, such as dabrafenib and trametinib, show promise for certain GBM subgroups, identifying drug combinations effective across the broader GBM population remains a challenge. Integrin-mediated signalling, particularly through Focal Adhesion Kinase (FAK), plays a pivotal role in GBM pathogenesis and invasion, making it a potential therapeutic target [1]. In our study, we utilized a chemogenomic screening approach to identify synergistic drug combinations that target FAK in glioblastoma. We initially employed a CRISPR-engineered GBM model to assess the effects of FAK depletion and discovered that combining FAK inhibitors with MEK inhibitors, particularly trametinib, demonstrated synergistic effects. This potent combination was validated through various 2D & 3D assays, including cell viability/apoptotic assessment, synergistic analysis, cellular imaging, and target engagement assays. The combination also effectively inhibited spheroid growth and invasion across a diverse panel of patient derived GBM stem cells. Molecular mechanisms underlying these effects included suppression of multiple kinase signalling pathways and enhanced apoptosis, elucidated using Reverse Phase Protein Array (RPPA) profiling and western blot validation. In vivo , the combination therapy significantly reduced tumour volume in orthotopic transplantation models. These findings suggest that combining FAK and MEK inhibitors represent a promising therapeutic strategy to overcome the challenges of GBM treatment.
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Abstract
Glioblastoma (GBM) is an aggressive brain tumour with limited treatment options and poor prognosis, largely due to its heterogeneity and the involvement of multiple intracellular signalling pathways that contribute to drug resistance. Standard therapies have not significantly improved patient outcomes over the past two decades. While recent advancements in targeted drug combination therapies, such as dabrafenib and trametinib, show promise for certain GBM subgroups, identifying drug combinations effective across the broader GBM population remains a challenge. Integrin-mediated signalling, particularly through Focal Adhesion Kinase (FAK), plays a pivotal role in GBM pathogenesis and invasion, making it a potential therapeutic target [1].
In our study, we utilized a chemogenomic screening approach to identify synergistic drug combinations that target FAK in glioblastoma. We initially employed a CRISPR-engineered GBM model to assess the effects of FAK depletion and discovered that combining FAK inhibitors with MEK inhibitors, particularly trametinib, demonstrated synergistic effects. This potent combination was validated through various 2D & 3D assays, including cell viability/apoptotic assessment, synergistic analysis, cellular imaging, and target engagement assays. The combination also effectively inhibited spheroid growth and invasion across a diverse panel of patient derived GBM stem cells. Molecular mechanisms underlying these effects included suppression of multiple kinase signalling pathways and enhanced apoptosis, elucidated using Reverse Phase Protein Array (RPPA) profiling and western blot validation. In vivo, the combination therapy significantly reduced tumour volume in orthotopic transplantation models. These findings suggest that combining FAK and MEK inhibitors represent a promising therapeutic strategy to overcome the challenges of GBM treatment.
Competing Interest Statement
N.O.C discloses the following patents: Combination of a MEK inhibitor and the Src kinase inhibitor AZD0530 for use in the treatment of cancer. Patent No. PCT/GB2007004927. EP3298015B1, JP6684831B2, US10294227B2, CN107849050B, and CA3021550A1 pertaining to the discovery of the Src Family Kinase inhibitor eCF506/NXP900 that have been licensed to Nuvectis Pharma Inc. N.O.C hold grants from Nuvectis Pharma to study eCF06/NXP900 outside of the submitted work. M.C.F and N.O.C are shareholders and have acted as advisors of Amplia Therapeutics Ltd.
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