Purpose EMT has been associated with metastatic spread and EGFR inhibitor resistance. We developed and validated a robust 76-gene EMT signature using gene expression profiles from four platforms using NSCLC cell lines and patients treated in the BATTLE study. Methods We conducted an integrated gene expression, proteomic, and drug response analysis using cell lines and tumors from NSCLC patients. A 76-gene EMT signature was developed and validated using gene expression profiles from four microarray platforms of NSCLC cell lines and patients treated in the BATTLE (Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination) study, and potential therapeutic targets associated with EMT were identified. Results Compared with epithelial cells, mesenchymal cells demonstrated significantly greater resistance to EGFR and PI3K/Akt pathway inhibitors, independent of EGFR mutation status, but more sensitivity to certain chemotherapies. Mesenchymal cells also expressed increased levels of the receptor tyrosine kinase Axl and showed a trend towards greater sensitivity to the Axl inhibitor SGI-7079, while the combination of SGI-7079 with erlotinib reversed erlotinib resistance in mesenchymal lines expressing Axl and in a xenograft model of mesenchymal NSCLC. In NSCLC patients, the EMT signature predicted 8-week disease control in patients receiving erlotinib, but not other therapies. Conclusion We have developed a robust EMT signature that predicts resistance to EGFR and PI3K/Akt inhibitors, highlights different patterns of drug responsiveness for epithelial and mesenchymal cells, and identifies Axl as a potential therapeutic target for overcoming EGFR inhibitor resistance associated with the mesenchymal phenotype

B-cell receptor (BCR) signaling is a critical pathway in the pathogenesis of several B-cell malignancies, including chronic lymphocytic leukemia (CLL), and can be targeted by inhibitors of BCRassociated kinases, such as Bruton tyrosine kinase (Btk). PCI-32765, a selective, irreversible Btk inhibitor, is a novel, molecularly targeted agent for patients with B-cell malignancies, and is particularly active in patients with CLL. In this study, we analyzed the mechanism of action of PCI-32765 in CLL, using in vitro and in vivo models, and performed correlative studies on specimens from patients receiving therapy with PCI-32765. PCI-32765 significantly inhibited CLL cell survival, DNA synthesis, and migration in response to tissue homing chemokines (CXCL12, CXCL13 IntroductionChronic lymphocytic leukemia (CLL), the most common leukemia in western societies, is characterized by the accumulation of mature, CD5 ϩ CD23 ϩ monoclonal B lymphocytes in the blood, secondary lymphatic tissues, and the bone marrow. 1 Proliferating CLL cells, which account for approximately 0.1% to 1% of the CLL clone, 2 are typically found within microanatomical structures called proliferation centers or pseudofollicles, 3 where CLL cells interact with accessory cells (ie, stromal cells or T cells), thereby receiving survival and growth signals. 4 Such external signals from the leukemia microenvironment can supplement intrinsic oncogenic lesions, thereby promoting maintenance and expansion of the CLL clone. 3,5,6 Among the various external stimuli in the tissue microenvironments, B-cell receptor (BCR) activation and signaling, particularly in lymphatic tissues, 6 is a central pathologic mechanism, even though the precise mechanism of BCR stimulation and the nature of the antigen(s) that activate the BCRs remain obscure. 1,7 The most direct evidence for the importance of BCR signaling in CLL comes from recent comparative gene expression profiling (GEP) data that revealed BCR signaling as the most prominent pathway activated in CLL cells isolated from lymphatic tissues. 6 These GEP changes displayed remarkable similarity to GEP changes of CLL cells cocultured with monocyte-derived nurselike cells (NLC), 8 a system for studying the impact of the lymphatic tissue microenvironment in CLL in vitro. Additional evidence for the importance of BCR signaling in CLL comes from the observation that important CLL risk factors have functional links to the BCRs. The mutation status of the IgV H segments of the BCR distinguishes "mutated" (M-CLL) from "unmutated" CLL (U-CLL), with a low or high risk for disease progression, respectively, each accounting for approximately 50% of the patients. ZAP-70 is predominantly expressed in U-CLL cases, 9 and ZAP-70 expression is associated with enhanced BCR signaling. 10 Furthermore, CLL patients express restricted sets of BCRs, as determined by BCR sequencing. These BCRs have immunoglobulin (Ig) heavy-chain variable (V) gene sequences that are identical or stereotyped in subsets of patients, 11,12 suggesting that these BCR...

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