Heterogeneous expression of amplified and mutated EGFR presents a substantial challenge for the effective use of EGFR-directed therapeutics. To address this, we used human and murine GBM cell lines, patient derived xenograft (PDX) models and clinical specimens from GBM patients, to describe an active attenuation in sensitivity to EGFR tyrosine kinase inhibitors (TKIs) mediated by EGFRvIII-driven production of IL-6. Mechanistically, activation of the IL-6 common receptor, gp130, expressed on wtEGFR cells, promotes NF-κB activation and subsequent expression of a pro-survival gene target, survivin (BIRC5), through deposition of NF-κB in complex with BRD4 at its promoter. This signaling axis is efficiently uncoupled by the BET inhibitor JQ1, leading to inhibition of survivin expression and restored sensitivity to anti-EGFR therapy. These results underscore that in addition to cell intrinsic mechanisms, attenuation to therapy can also occur through extrinsic cues fostered by interclonal tumor cell communication within the tumor ecosystem. Understanding heterotypic tumor cell interactions, as exemplified by the EGFR mutational landscape found in GBM, will better inform strategies to overcome therapy resistance commonly encountered for this tumor.