Genetic alterations in the kinase domain of the epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) patients are associated with sensitivity to treatment with small molecule tyrosine kinase inhibitors. Although first-generation reversible, ATP-competitive inhibitors showed encouraging clinical responses in lung adenocarcinoma tumors harboring such EGFR mutations, almost all patients developed resistance to these inhibitors over time. Such resistance to firstgeneration EGFR inhibitors was frequently linked to an acquired T790M point mutation in the kinase domain of EGFR, or upregulation of signaling pathways downstream of HER3. Overcoming these mechanisms of resistance, as well as primary resistance to reversible EGFR inhibitors driven by a subset of EGFR mutations, will be necessary for development of an effective targeted therapy regimen. Here, we show that BIBW2992, an anilino-quinazoline designed to irreversibly bind EGFR and HER2, potently suppresses the kinase activity of wild-type and activated EGFR and HER2 mutants, including erlotinib-resistant isoforms. Consistent with this activity, BIBW2992 suppresses transformation in isogenic cell-based assays, inhibits survival of cancer cell lines and induces tumor regression in xenograft and transgenic lung cancer models, with superior activity over erlotinib. These findings encourage further testing of BIBW2992 in lung cancer patients harboring EGFR or HER2 oncogenes.

The EGFR T790M mutation has been identified in tumors from lung cancer patients that eventually develop resistance to erlotinib. In this study, we generated a mouse model with doxycycline-inducible expression of a mutant EGFR containing both L858R, an erlotinib-sensitizing mutation, and the T790M resistance mutation (EGFR TL). Expression of EGFR TL led to development of peripheral adenocarcinomas with bronchioloalveolar features in alveoli as well as papillary adenocarcinomas in bronchioles. Treatment with an irreversible EGFR tyrosine kinase inhibitor (TKI), HKI-272, shrunk only peripheral tumors but not bronchial tumors. However, the combination of HKI-272 and rapamycin resulted in significant regression of both types of lung tumors. This combination therapy may potentially benefit lung cancer patients with the EGFR T790M mutation.

Mutations in the HER2 kinase domain have been identified in human clinical lung cancer specimens. Here we demonstrate that inducible expression of the most common HER2 mutant (HER2 YVMA ) in mouse lung epithelium causes invasive adenosquamous carcinomas restricted to proximal and distal bronchioles. Continuous expression of HER2 YVMA is essential for tumor maintenance, suggesting a key role for HER2 in lung adenosquamous tumorigenesis. Preclinical studies assessing the in vivo effect of erlotinib, trastuzumab, BIBW2992, and/or rapamycin on HER2 YVMA transgenic mice or H1781 xenografts with documented tumor burden revealed that the combination of BIBW2992 and rapamycin is the most effective treatment paradigm causing significant tumor shrinkage. Immunohistochemical analysis of lung tumors treated with BIBW2992 and rapamycin combination revealed decreased phosphorylation levels for proteins in both upstream and downstream arms of MAPK and Akt/mTOR signaling axes, indicating inhibition of these pathways. Based on these findings, clinical testing of the BIBW2992/rapamycin combination in non-small cell lung cancer patients with tumors expressing HER2 mutations is warranted. lung cancer ͉ murine model H ER2 (erbB-2/neu) is a member of the erbB receptor tyrosine kinase family that also includes EGFR (HER1/erbB-1), HER3 (erbB-3), and HER4 (erbB-4). Whereas these family members usually dimerize upon ligand binding, HER2, for which no ligand is reported, exists mainly in its active conformation. HER2 readily heterodimerizes with other erbB family members and is considered to be the preferred dimerization partner for EGFR, HER3, and HER4 (1). In addition to ligand binding, receptor dimerization can be induced by a high concentration of receptors at the plasma membrane or by kinase domain mutations (2, 3), resulting in receptor activation by the transphosphorylation of tyrosine residues in the C terminus of the respective molecules (4). The phosphorylated residues act as docking sites for an array of downstream signaling molecules activating several biochemical pathways such as the MAPK, the PI3K/Akt/mTOR, the phospholipase C, and the Jak/Stat signaling pathways (2, 3, 5). These signal transduction cascades in concert regulate cellular processes such as proliferation, apoptosis, angiogenesis, migration, adhesion, and differentiation.Mutations in the HER2 kinase domain have been reported in lung adenocarcinomas at a relatively low frequency of 2-4% (6, 7). Thus far, majority of the HER2 mutations identified in non-small cell lung cancer (NSCLC) samples are in-frame duplications or insertions in a small 8-codon region (codons 774-781 or 775-782) on exon 20. These mutations are analogous to the duplications/ insertions in the 9-codon region of exon 20 in EGFR, translating to the C terminus of the ␣C helix in the TK (tyrosine kinase) domain. Based on this similarity, it has been postulated (7) that mutations in HER2 cause a shift in the helical axis that narrows the ATP binding cleft, resulting in both increased TK activity and...

Various LV functional parameters were measured with multi-detector row CT with a segmental approach, and measurements correlated and agreed with those obtained with MR imaging. Moreover, functional analysis with multi-detector row CT was more accurate than that with two-dimensional echocardiography or ECG-gated SPECT.

The epidermal growth factor receptor (EGFR) secondary kinase domain T790M non-small cell lung cancer (NSCLC) mutation enhances receptor catalytic activity and confers resistance to the reversible tyrosine kinase inhibitors gefitinib and erlotinib. Currently, irreversible inhibitors represent the primary approach in clinical use to circumvent resistance. We show that higher concentrations of the irreversible EGFR inhibitor CL-387,785 are required to inhibit EGFR phosphorylation in T790M-expressing cells compared with EGFR mutant

Delayed enhanced MRI is considered a useful method for the early identification of cardiac sarcoidosis. Delayed hyperenhancement is frequently associated with a reduction of regional wall motion and thallium-201 perfusion defects.

The cholinesterase inhibitor neostigmine markedly impairs upper airway dilator volume, genioglossus muscle function, diaphragmatic function, and breathing when given after recovery from vecuronium-induced neuromuscular block.

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