Dres-09. Mechanisms of Resistance to Egfr Inhibition Reveal Metabolic Vulnerabilities in Human Gbm
Year: 2016
Type: conference-abstract
Abstract: Therapeutic targeting of EGFR signaling in GBM has had largely disappointing results in the clinic. We sought to identify cell vulnerabilities that could be targeted in combination with EGFR. Using a murine model for GBM, primary patient derived xenografts (PDXs), and human tumors we identify altered lipid metabolism and intratumoral heterogeneity as important mechanisms of resistance to EGFR inhibition. In murine tumor progenitor cells (TPCs) driven by oncogenic EGFR, inhibition of EGFR selected for a tumor cell subpopulation with a highly invasive phenotype. This drug resistant subpopulation expressed several markers associated with chemoresistance including increased expression of enzymes responsible for detoxification of lipid peroxidation products. As strong oncogenic signaling is associated with increased de novo lipogenesis, we hypothesized EGFR inhibition may increase lipid peroxidation. Indeed, upon EGFR inhibition we observed increased generation of toxic lipid peroxidation products. Cell subpopulations with increased metabolism of these toxic products demonstrated increased drug resistance and a pro-invasive phenotype upon EGFR inhibition. Examination of 92 human GBM and 9 PDX lines revealed robust expression of enzymes able to detoxify these lipid peroxidation products in a significant subset of tumors. In a PDX with EGFR signaling, EGFR inhibition increased enzyme expression and increased tumor cell invasion in an enzyme-dependent manner. Interestingly, a PDX with high endogenous enzyme expression was highly sensitive to enzyme inhibition as demonstrated by decreased tumor cell invasion and decreased cell survival. These data identify expression of enzymes that detoxify lipid peroxidation products as a mechanism of resistance to EGFR inhibition and reveal a potential metabolic vulnerability to exploit therapeutically.
Source: Neuro-Oncology
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4237417899