EGFR-targeted therapy-induced resistance mechanism in glioblastoma

Analysis of mouse glioma tumors (in RAG1-/- mouse host) overexpressing Control(C) or Slug(S) viruses, and treated with doxycyclin(D) to turn off EGFRviii expression. Results provide insight into molecular basis of EGFRviii targeted therapy-induced resistence in GBM. By utilizing animals engineered with doxycycline (dox)-off oncogenic EGFRvIII transgene and conditional Ink4a/Arf and Pten alleles (Nestin-CreERT2; Ink4aL/L; PtenL/L; hGFAP_tTA; tetO-EGFRvIII, designated iEIP), we previously demonstrated that sustained oncogenic EGFR signaling was required for maintenance of EGFR-driven glioma progression and suppression of oncogenic EGFRvIII transgene expression induces tumor regression. But despite of a robust initial response, the regressed tumors relapsed inevitably. The finding that relapsed tumors had escaped oncogenic EGFR signaling addiction promoted our search for potential genetic events that might fuel the resistance development. Three relapse and two matched treatment-naïve tumors derived from the same parental line were analyzed by whole exome sequencing. Glioma mRNA profiles of Control, ControlDox, Slug, SlugDox were generated by deep sequencing, in triplicate, using Illumina HiSeq 4000. To examine potential changes in mutation and copy number landscapes in replased tumors recovered from oncogenic EGFR suppression, we performed exome sequencing on three cultured tumor cells from relapsed tumors (147, 175, relapse 8) as well as two untreated glioma samples (QX, 2QX).