Rational combinatorial targeted therapies for cancer are likely required to achieve potent durable responses. We mapped the interactome of a tumor-enriched isoform of Hsp90 (teHsp90), using a pharmacoproteomics approach trapping teHsp90 with the small molecule PU-H71. This strategy yielded enrichment of the proximal B cell receptor (BCR) signalosome. In functional assays we identified a novel mechanism for teHsp90 in facilitating BCR signaling dynamics by enabling phosphorylation of key BCR signalosome components including SYK and BTK. Consequently, PU-H71 attenuated BCR signaling, calcium flux and NF-?B signaling, ultimately leading to growth arrest in BCR-dependent ABC DLBCL cells. Combined exposure to PU-H71 and BCR pathway inhibitors, most notably ibrutinib, resulted in more potent suppression of BCR signaling than either drug alone in ABC DLBCL cell lines. PU-H71 combined with ibrutinib correspondingly induced synergistic killing of ABC DLBCL cell lines, primary human specimens ex vivo, and lymphoma xenografts in vivo, without significant toxicity. Pharmacoproteome driven rational combination therapy thus provides the basis for more potent BCR-directed therapy for ABC-DBLCL patients. teHsp90 inhibition induces broad attenuation of lateral pathways that contribute to the greater BCR signaling network and DLBCL survival such as PI3K/AKT and ERK signaling, likely contributing to the synergistic growth inhibition induced by the PU-H71-ibrutinib combination treatment. In viability assays of many different combinations of BCR pathway inhibitors in ABC DLBCL cell lines, we observed differential combination growth inhibition effects that suggest general principles required for rational combination treatment design. Namely, inhibition of lateral pathways within a signaling network induces maximal synergistic growth arrest.