PDGFRb regulation as a mode of resistance to EGFR inhibition in Glioblastoma

摘要: Glioblastoma is the most common and aggressive form of malignant primary brain tumor in adults. The epidermal growth factor receptor (EGFR) a compelling molecular target glioblastoma, because it amplified, over-expressed, or mutated nearly 50% patients. Monotherapy clinical trials with EGFR inhibitors have shown benefit only subset patients (10-15)% limited duration response. We that glioblastoma whose tumors mutant receptor, EGFRvIII, not lost PTEN suppressor protein are significantly more likely to respond we identified circuitry underlying this response1. This work, along studies from others demonstrates resistance may be mediated through maintenance signal flux PI3K pathway2,3. Utilizing variety powerful resources - isogenic cell lines, low passage patient cells, mouse models samples include treated my work focused on identifying mechanisms kinase targeted combination therapies suppress it. demonstrate signaling potently suppresses PDGFR-beta transcription expression vitro vivo inhibition releases suppression vivo. relevance by showing elevated PDGFR levels GBM EGFR/her2 inhibitor lapatinib phase I trial. Furthermore, use series genetic pharmacologic approaches show EGFR-dependent mTORC1 maintains EGFR-inhibitor models. These results provide mechanistic basis which GBMs switch response suggest dual targeting required for effective treatment. has potential explain clinically important mechanism therapy develop potent promoting long term disease suppression.