Non-small cell lung cancers (NSCLCs) with activating mutations in the kinase domain of the epidermal growth factor receptor (EGFR) demonstrate dramatic, but transient, responses to the reversible tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva). Some recurrent tumors have a common secondary mutation in the EGFR kinase domain, T790M, conferring drug resistance, but in other cases the mechanism underlying acquired resistance is unknown. In studying multiple sites of recurrent NSCLCs, we detected T790M in only a small percentage of tumor cells. To identify additional mechanisms of acquired resistance to gefitinib, we used NSCLC cells harboring an activating EGFR mutation to generate multiple resistant clones in vitro. These drug-resistant cells demonstrate continued dependence on EGFR and ERBB2 signaling for their viability and have not acquired secondary EGFR mutations. However, they display increased internalization of ligand-activated EGFR, consistent with altered receptor trafficking. Although gefitinib-resistant clones are cross-resistant to related anilinoquinazolines, they demonstrate sensitivity to a class of irreversible inhibitors of EGFR. These inhibitors also show effective inhibition of signaling by T790M-mutant EGFR and killing of NSCLC cells with the T790M mutation. Both mechanisms of gefitinib resistance are therefore circumvented by irreversible tyrosine kinase inhibitors. Our findings suggest that one of these, HKI-272, may prove highly effective in the treatment of EGFR-mutant NSCLCs, including tumors that have become resistant to gefitinib or erlotinib.drug resistance ͉ molecular targeted therapy ͉ non-small cell lung cancer ͉ tyrosine kinase inhibitor

Somatic activating mutations in EGFR identify a subset of non-small cell lung cancer that respond to tyrosine kinase inhibitors. Acquisition of drug resistance is linked to a specific secondary somatic mutation, EGFR T790M. Here we describe a family with multiple cases of non-small cell lung cancer associated with germline transmission of this mutation. Four of six tumors analyzed showed a secondary somatic activating EGFR mutation, arising in cis with the germline EGFR mutation T790M. These observations implicate altered EGFR signaling in genetic susceptibility to lung cancer.

The mechanisms underlying tumoral secretion of signaling molecules into the microenvironment, which modulates tumor cell fate, angiogenesis, invasion, and metastasis, are not well understood. Aberrant expression of transcription factors, which has been implicated in the tumorigenesis of several types of cancers, may provide a mechanism that induces the expression of growth and angiogenic factors in tumors, leading to their local increase in the tumor microenvironment, favoring tumor progression. In this report, we demonstrate that the transcription factor HOXB9 is overexpressed in breast carcinoma, where elevated expression correlates with high tumor grade. HOXB9 induces the expression of several angiogenic factors (VEGF, bFGF, IL-8, and ANGPTL-2), as well as ErbB (amphiregulin, epiregulin, and neuregulins) and TGF-ß, which activate their respective pathways, leading to increased cell motility and acquisition of mesenchymal phenotypes. In vivo, HOXB9 promotes the formation of large, well-vascularized tumors that metastasize to the lung. Thus, deregulated expression of HOXB9 contributes to breast cancer progression and lung metastasis by inducing several growth factors that alter tumor-specific cell fates and the tumor stromal microenvironment.ultifunctional cytokines, such as TGF-β and ErbB, and angiogenic factors secreted by the tumor and stroma initiate a dynamic interaction between the tumor and its microenvironment that modulates tumor growth and cell fates, angiogenesis, invasion, and distal metastasis-processes critical for disease progression. Little is known about the mechanisms underlying tumoral secretion of these signaling molecules. Aberrantly expressed transcription factors, implicated in the tumorigenesis of several types of cancers, may provide a mechanism to induce the expression of growth and angiogenic factors in tumors, leading to their local increase in the tumor microenvironment.The class I HOX gene family comprises 39 members with a shared, highly conserved 61-amino acid homeodomain motif. These genes are important regulators of development, and their role in neoplastic transformation and tumor progression is being increasingly recognized (1). A number of HOX genes are expressed in the normal mammary gland. Mouse knockouts suggest that the ninth paralogous HOX genes play a role in mammary gland development (2). Mice homozygous for loss of HOXB9 exhibit developmental defects and a decline in newborn survival (3); loss of HOXA9, HOXB9, and HOXD9 impairs branching of the breast epithelium and lobuloalveolar development, leading to a failure to nurse pups (2). Although aberrant expression of some HOX members has been demonstrated in breast tumors (4-13), the functional consequence of deregulated HOX expression in cancer progression is not well understood.HOX genes regulate several cellular processes, including angiogenesis and maintenance of cell fate (14-16). Epithelial-tomesenchymal transition (EMT) is an embryonic morphogenetic conversion that is recapitulated during tumor progression. Durin...