Dataset Information

Heterogeneous EGFR, CDK4, MDM4, and PDGFRA Gene Expression Profiles in Primary GBM: No Association with Patient Survival.

ABSTRACT: BACKGROUND:The prognostic impact of the expression profile of genes recurrently amplified in glioblastoma multiforme (GBM) remains controversial. METHODS:We investigated the RNA gene expression profile of epidermal growth factor receptor (EGFR), cyclin-dependent kinase 4 (CDK4), murine doble minute 4 (MDM4), and platelet derived growth factor receptor alpha (PDGFRA) in 83 primary GBM tumors vs. 42 normal brain tissue samples. Interphase FISH (iFISH) analysis for the four genes, together with analysis of intragenic deletions in EGFR and PDGFRA, were evaluated in parallel at the DNA level. As validation cohort, publicly available RNA gene expression data on 293 samples from 10 different GBM patient series were also studied. RESULTS:At the RNA level, CDK4 was the most frequently overexpressed gene (90%) followed by EGFR (58%) and PDGFRA (58%). Chromosome 7 copy number alterations, i.e., trisomy (49%) and polysomy (44%), showed no clear association with EGFR gene expression levels. In turn, intragenic EGFR deletions were found in 39 patients (47%), including EGFRvIII (46%) in association with EGFRvIVa (4%), EGFRvII (2%) or other EGFR deletions (3%) and PDGFRA deletion of exons 8-9 was found in only two tumors (2%). CONCLUSIONS:Overall, none of the gene expression profiles and/or intragenic EGFR deletions showed a significant impact on overall survival of GBM supporting the notion that other still unraveled features of the disease might play a more relevant prognostic role in GBM.

SUBMITTER: Gonzalez-Tablas M

PROVIDER: S-EPMC7016708 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Heterogeneous <i>EGFR</i>, <i>CDK4</i>, <i>MDM4</i>, and <i>PDGFRA</i> Gene Expression Profiles in Primary GBM: No Association with Patient Survival.

González-Tablas María M Arandia Daniel D Jara-Acevedo María M Otero Álvaro Á Vital Ana-Luisa AL Prieto Carlos C González-Garcia Nerea N Nieto-Librero Ana Belén AB Tao Herminio H Pascual Daniel D Ruiz Laura L Sousa Pablo P Galindo-Villardón Purificación P Orfao Alberto A Tabernero María Dolores MD

Cancers 20200117 1

<h4>Background</h4>The prognostic impact of the expression profile of genes recurrently amplified in glioblastoma multiforme (GBM) remains controversial.<h4>Methods</h4>We investigated the RNA gene expression profile of epidermal growth factor receptor (<i>EGFR</i>), cyclin-dependent kinase 4 (<i>CDK4</i>), murine doble minute 4 (<i>MDM4</i>), and platelet derived growth factor receptor alpha (<i>PDGFRA</i>) in 83 primary GBM tumors vs. 42 normal brain tissue samples. Interphase FISH (iFISH) ana ...[more]

PMID: 31963499

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Project description:BackgroundIn v-raf murine sarcoma viral oncogene homolog B1 (BRAF)-mutant colorectal cancer (CRC), encorafenib-cetuximab has been established as standard second-line therapy, but not all patients respond and the duration of response is relatively short. Overcoming intrinsic or acquired resistance to BRAF/EGFR inhibitors is crucial for enhancing treatment outcomes in metastatic BRAF-mutated CRC. The aim of the study is to investigate the resistance mechanisms in BRAF-mutant CRC patient refractory to BRAF/EGFR targeted therapy.MethodsWe established patient-derived cells (PDCs) from a patient with BRAF/PTEN-mutant metastatic colon cancer who progressed rapidly on encorafenib plus cetuximab. To explore potential treatment options for inherent resistance caused by simultaneous PTEN mutation in BRAF-mutated CRC, we conducted cell viability assays using PDCs treated with encorafenib-cetuximab in combination with a cyclin-dependent kinase-4 and 6 (CDK4/6) inhibitor.ResultsThe patient's tumor had concurrent PTEN loss-of-function alteration at diagnosis and PDCs were generated from ascites after resistance to the BRAF/EGFR inhibitor. The PDCs were resistant to the encorafenib-cetuximab combination even at a high concentration of cetuximab (up to 500 µg/mL). Adding the CDK4/6 inhibitor, ribociclib, to encorafenib-cetuximab showed a synergistic effect in a proliferation assay. Ribociclib plus encorafenib-cetuximab represented a significantly lower expression of Ki-67 compared to the dual combination alone. An MTS assay showed that triplet therapy with ribociclib, encorafenib, and cetuximab suppressed cell viability more efficiently than the two-drug combinations. Investigating the combined effect of triplet therapy using the calculated combination index (CI) showed that ribociclib had a synergistic effect with encorafenib-cetuximab when applied to PDCs with a concurrent BRAF/PTEN mutation.ConclusionsOur results suggest that combining the CDK4/6 inhibitor with the BRAF/EGFR inhibitor might be a novel treatment strategy for concomitant BRAF and PTEN-mutant CRC.

Dataset Information

Heterogeneous EGFR, CDK4, MDM4, and PDGFRA Gene Expression Profiles in Primary GBM: No Association with Patient Survival.

Publications

Heterogeneous <i>EGFR</i>, <i>CDK4</i>, <i>MDM4</i>, and <i>PDGFRA</i> Gene Expression Profiles in Primary GBM: No Association with Patient Survival.

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