We show that two commonly occurring epidermal growth factor receptor (EGFR) somatic mutations, L858R and an in-frame deletion mutant, Del(746-750), exhibit distinct enzymatic properties relative to wild-type EGFR and are differentially sensitive to erlotinib. Kinetic analysis of the purified intracellular domains of EGFR L858R and EGFR Del(746-750) reveals that both mutants are active but exhibit a higher K M for ATP and a lower K i for erlotinib relative to wild-type receptor. When expressed in NR6 cells, a cell line that does not express EGFR or other ErbB receptors, both mutations are ligand dependent for receptor activation, can activate downstream EGFR signaling pathways, and promote cell cycle progression. As expected from the kinetic analysis, the EGFR Del(746-752) is more sensitive to erlotinib inhibition than the EGFR L858R mutant. Further characterization shows that these mutations promote ligand-dependent and anchorageindependent growth, and cells harboring these mutant receptors form tumors in immunocompromised mice. Analysis of tumor lysates reveals that the tumorigenicity of the mutant EGFR cell lines may be due to a differential pattern of mutant EGFR autophosphorylation as compared with wild-type receptor. Significant inhibition of tumor growth, in mice harboring wild-type EGFR receptors, is only observed at doses of erlotinib approaching the maximum tolerated dose for the mouse. In contrast, the growth of mutant tumors is inhibited by erlotinib treatment at approximately one third the maximum tolerated dose. These findings suggest that EGFR somatic mutations directly influence both erlotinib sensitivity and cellular transformation. (Cancer Res 2006; 66(16): 8163-71)

A striking feature of colon tumors is the significant reduction of goblet cells. Although targeted deletion of Math1 in mice leads to a loss of intestinal secretory cells, including goblet cells, the role of Hath1 in colon tumorigenesis remains unknown. Here we report that Hath1, the human ortholog of Math1, was dramatically down-regulated in colon tumor samples and colon cancer cell lines. Overexpression of Hath1 in HT29, an aggressive colon cancer cell line, resulted in a significant inhibition on cell proliferation, anchorage-independent growth in soft agar and, more importantly, growth of human colon cancer cell xenografts in athymic nude mice. Such inhibition was accompanied by altered expression of a goblet cell differentiation marker, MUC2, and cell cycle regulators cyclin D1 and p27 kip1 . Hath1 expression also was up-regulated on inhibition of the Wnt pathway, which has been well implicated in colon tumorigenesis. Hence, this study suggests that Hath1 may be a novel factor downstream of the Wnt pathway capable of suppressing anchorage-independent growth of colon cancer cell lines. More importantly, this study is the first to establish a link between down-regulation of Hath1 expression and colon tumorigenesis.

Despite the availability of new targeted therapies, ductal pancreatic adenocarcinoma continues to carry a poor prognosis. Carcinoembryonic antigen-related cell adhesion molecule (CEACAM)6 has been reported as a potential biomarker and therapy target for this malignancy. We have evaluated CEACAM6 as a potential therapy target, using an antibody-drug conjugate (ADC). Expression of CEACAM6 in pancreatic adenocarcinomas was determined using immunohistochemistry on tissue microarrays. The expression pattern in granulocytes and granulocytic precursors was measured by flow cytometry. Murine xenograft and non-human primate models served to evaluate efficacy and safety, respectively. Robust expression of CEACAM6 was found in > 90% of invasive pancreatic adenocarcinomas as well as in intraepithelial neoplastic lesions. In the granulocytic lineage, CEACAM6 was expressed at all stages of granulocytic maturation except for the early lineage-committed precursor cell. The anti-CEACAM6 ADC showed efficacy against established CEACAM6-expressing tumours. In non-human primates, antigen-dependent toxicity of the ADC consisted of dose-dependent and reversible depletion of granulocytes and their precursors. This was associated with preferential and rapid localization of the antibody in bone marrow, as determined by sequential in vivo PET imaging of the radiolabelled anti-CEACAM6. Localization of the radiolabelled tracer could be attenuated by predosing with unlabelled antibody confirming specific accumulation in this compartment. Based on the expression pattern in normal and malignant pancreatic tissues, efficacy against established tumours and limited and reversible bone marrow toxicity, we propose that CEACAM6 should be considered for an ADC-based therapy approach against pancreatic adenocarcinomas and possibly other CEACAM6-positive neoplasms.

This is a review of the fine‐needle aspirates (FNAs) of nine pilomatrixomas (PMs) found in a series of 1,500 FNAs performed on skin nodules. The objective is to determine and list the cytologic findings that might mislead the less‐experienced cytopathologist and to give him advice on how to avoid such errors. The following recommendations are made: 1) The FNAs should be carried out and the smears interpreted by the same person. 2) Clinical data, particularly age and location, are of paramount importance. 3) Shadow cells are pathognomonic of PMs. 4) Basaloid nuclei with prominent nucleoli should not be overdiagnosed. 5) Use both Papanicolaou and Diff‐Quik stains. 6) Think of PM when performing and interpreting aspirations from subcutaneous growths located in the head and neck of young persons. Diagn Cytopathol 1996;14:75–83. © 1996 Wiley‐Liss, Inc.

This is a review of the fine‐needle aspirates (FNAs) of nine pilomatrixomas (PMs) found in a series of 1,500 FNAs performed on skin nodules. The objective is to determine and list the cytologic findings that might mislead the less‐experienced cytopathologist and to give him advice on how to avoid such errors. The following recommendations are made: 1) The FNAs should be carried out and the smears interpreted by the same person. 2) Clinical data, particularly age and location, are of paramount importance. 3) Shadow cells are pathognomonic of PMs. 4) Basaloid nuclei with prominent nucleoli should not be overdiagnosed. 5) Use both Papanicolaou and Diff‐Quik stains. 6) Think of PM when performing and interpreting aspirations from subcutaneous growths located in the head and neck of young persons. Diagn Cytopathol 1996;14:75–83. © 1996 Wiley‐Liss, Inc.