Abstract Glioblastoma (GBM), a particularly aggressive form of primary brain tumor, has poor survival due to a lack of effective treatments and high recurrence. Epidermal growth factor receptor (EGFR) (mapped to 7p 11.2), is frequently amplified and mutated (>50%) in GBM, and is suggested as a potential therapeutic target. To correlate chemo-vulnerability with genomic aberrations and further determine biomarkers for targeted therapies, a panel of seven EGFR tyrosine kinase inhibitors were tested in a selected nine human GBM patient-derived xenograft (PDX) panel; these preclinical models harbor different mutation combinations of CDKN2A deletion (C), PTEN deletion (P), wild-type EGFR (E) and/or EGFRvIII (Ev3) overexpression. A single agent drug dose response assay (DDR) was performed on GBM PDX neurospheres using drug concentrations ranging from 100uM to 0.5nM with a 12-point serial 3-fold dilution scheme. The cytotoxic efficacy of EGFR inhibition was dependent on both the PDX line and the EFGR inhibitor applied. GBM59 and GBM76 – both triple CEv3P mutants – were the most responsive to EGFR inhibition relative to the other GBM models tested. For GBM59, the IC50 values of afatinib, canertinib and neratinib, were sub-micromolar, and low micromolar (<3uM) for erlotinib, gefitinib and lapatinib. GBM76 had IC50 values of 1-8uM with all seven EGFR inhibitors including AZD3759. However, GBM155 and GBM126 with CEv3 but wildtype PTEN only responded to afatinib, canertinib and neratinib at low micromolar IC50 values (<3uM) but not to erlotinib, gefitinib and lapatinib. A deletion in PTEN may sensitize GBM cells with CEv3 mutations to erlotinib, gefitinib and lapatinib in vitro. The other group of GBM PDX lines (C only) represented by GBM122, GBM150 and GBM182 responded well to afatinib, canertinib and neratinib with IC50 values of 2- 9uM. GBM156 with CE had a similar profile to the group of C only or CEv3. GBM56 with CP showed the most resistance with mild responses to afatinib, canertinib and neratinib, as observed in its high micromolar IC50 values (6-9uM). Overall, neratinib is the most effective compound among the tested EGFR inhibitors based on IC50 values. Canertinib, the triple tyrosine kinase inhibitor against EGFR/HER2/ErbB-4, is the second most effective agent. Afatinib has similar drug efficacy to canertinib. All three compounds moderately inhibit all GBM PDX lines. The drug response mechanism and its correlation with the mutation status of CDKN2A, EGFR, and PTEN will be further investigated cross a broad array of GBM PDX models. Supported by NIH NCI R01 CA204136 Citation Format: Nanyun Tang, George Reid, C Ryan Miller, Michael E. Berens. Selective vulnerability of GBM PDX to a panel of EGFR tyrosine kinase inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3681.