Dual Targeting of EGFR and MTOR pathways inhibits glioblastoma growth by modulating the tumor microenvironment

In the current study we focused on identifying an effective therapeutic regimen for a cohort of human-derived GBM models driven by alterations in the EGFR pathway. Pharmacological testing based on the genomics characteristic of each patient-derived model demonstrated that no single drug is efficacious in inhibiting tumor cell viability in culture. Combining two targeting agents Erlotinib (Tarceva) and MLN0128 (investigational MTOR inhibitor) resulted in effective tumor cell killing across several GBM PDX- derived culture models. Mechanistically, inhibition of p-ERK, p-AKT and RSK pathways underlie the combinatorial drug effects in culture. Using an orthotopic primary-GBM model, we show that the two drugs combined resulted in significant improvement in survival, superior to either drug alone. Microarray RNA profiling of tumor tissues from treated mice showed that the anti-tumor efficacy of co-inhibiting EGFR and MTOR pathways was in part due to modulation of the tumor microenvironment, including downregulation of CCL2 and Periostin, and subsequent inhibition of TAM infiltration in treated tumors. RNA extracted from PDX samples from treated mice was used for microarray profiling. The samples include the following: 2 sham treated, 2 treated with the EGFR inhibitor Erlotinib, 2 treated with the MTOR inhibitor MLN0128 and 3 treated with a combination of Erlotinib and MLN0128. Analysis was focused on identifying DEG between treatment groups.