The epidermal growth factor receptor (EGFR) kinase inhibitors gefitinib and erlotinib are effective treatments for lung cancers with EGFR activating mutations, but these tumors invariably develop drug resistance. Here, we describe a gefitinib-sensitive lung cancer cell line that developed resistance to gefitinib as a result of focal amplification of the MET proto-oncogene. inhibition of MET signaling in these cells restored their sensitivity to gefitinib. MET amplification was detected in 4 of 18 (22%) lung cancer specimens that had developed resistance to gefitinib or erlotinib. We find that amplification of MET causes gefitinib resistance by driving ERBB3 (HER3)-dependent activation of PI3K, a pathway thought to be specific to EGFR/ERBB family receptors. Thus, we propose that MET amplification may promote drug resistance in other ERBB-driven cancers as well.

Purpose: The EML4-ALK fusion gene has been detected in f7% of Japanese non-small cell lung cancers (NSCLC). We determined the frequency of EML4-ALK in Caucasian NSCLC and in NSCLC cell lines. We also determined whether TAE684, a specific ALK kinase inhibitor, would inhibit the growth of EML4-ALK-containing cell lines in vitro and in vivo. Experimental Design: We screened 305 primary NSCLC [both U.S. (n = 138) and Korean (n = 167) patients] and 83 NSCLC cell lines using reverse transcription-PCR and by exon array analyses.We evaluated the efficacy of TAE684 against NSCLC cell lines in vitro and in vivo. Results: We detected four different variants, including two novel variants, of EML4-ALK using reverse transcription-PCR in 8 of 305 tumors (3%) and 3 of 83 (3.6%) NSCLC cell lines. All EML4-ALK-containing tumors and cell lines were adenocarcinomas. EML4-ALK was detected more frequently in NSCLC patients who were never or light (<10 pack-years) cigarette smokers compared with current/former smokers (6% versus 1%; P = 0.049). TAE684 inhibited the growth of one of three (H3122) EML4-ALK-containing cell lines in vitro and in vivo, inhibited Akt phosphorylation, and caused apoptosis. In another EML4-ALK cell line, DFCI032, TAE684 was ineffective due to coactivation of epidermal growth factor receptor and ERBB2. The combination of TAE684 and CL-387,785 (epidermal growth factor receptor/ERBB2 kinase inhibitor) inhibited growth and Akt phosphorylation and led to apoptosis in the DFCI032 cell line. Conclusions: EML4-ALK is found in the minority of NSCLC. ALK kinase inhibitors alone or in combination may nevertheless be clinically effective treatments for NSCLC patients whose tumors contain EML4-ALK.

Purpose: Somatic mutations in the epidermal growth factor receptor (EGFR) have been detected in patients with non^small cell lung cancer (NSCLC) and are associated with sensitivity to treatment with gefitinib or erlotinib. Our study explored the relationship between the two most common types of somatic EGFR mutations, exon 19 deletions and the L858R point mutation, and outcomes of patients following treatment with gefitinib or erlotinib. Experimental Design: Tumor specimens obtained before treatment with gefitinib or erlotinib were analyzed for EGFR mutations. Patients with exon19 deletion or L858R mutations were identified. The response rate, time to progression, and overall survival were determined for the two groups. Results: We identified 36 patients with NSCLC and an EGFR mutation who were treated with gefitinib or erlotinib. Patients with an exon 19 deletion had a significantly longer overall survival compared with patients with an L858R mutation (38 versus 17 months; P = 0.04). There were also trends toward higher response rate (73% versus 50%) and improved time to progression (24 versus 10 months) for the patients with an exon 19 deletion, although these were not independently significant in a multivariate analysis. A difference in response rate for patients treated with gefitinib compared with erlotinib was also noted [18 of 23 (78%) versus 3 of 9 (33%); P = 0.04]. No obvious difference in time to progression or overall survival was noted between gefitinib-and erlotinib-treated patients. Conclusions: Patients with NSCLC and EGFR exon 19 deletions have a longer survival following treatment with gefitinib or erlotinib compared with those with the L858R mutation. Pooling of greater numbers of patients and completion of prospective trials are needed to further define the predictive and prognostic roles of different EGFR mutations with respect to treatment with gefitinib, erlotinib, and other EGFR inhibitors.

The rapid increase in Pseudomonas (Burkholderia) cepacia infection in cystic fibrosis (CF) patients suggests epidemic transmission, but the degree of transmissibility remains controversial as conflicting conclusions have been drawn from studies at different CF centres. This report provides the first DNA sequence-based documentation of a divergent evolutionary lineage of P. cepacia associated with CF centre epidemics in North America (Toronto) and Europe (Edinburgh). The involved epidemic clone encoded and expressed novel cable (Cbl) pili that bind to CF mucin. The sequence of the cblA pilin subunit gene carried by the epidemic isolates proved to be invariant. Although it remains to be determined how many distinct, highly transmissible lineages exist, our results provide both a DNA sequence and chromosomal fingerprint that can be used to screen for one such particularly infectious, transatlantic clone.

HIV and human papillomavirus (HPV) coinfected patients are at high risk of developing precancerous anal lesions (anal intraepithelial neoplasia) and anal malignancies. 1 The natural history (that is, progression and persistence) of HPV-associated lesions is accelerated by HIV-related immunosuppression, which may result in the reactivation of previously acquired HPV infection and loss of control of HPV viral replication. 2 The longer life expectancy of these coinfected patients in the era of HAART provides an opportunity for invasive anal carcinoma to develop from its dysplastic precursor. The prognosis of anal squamous cell carcinoma is poor in HIV-positive patients, who often present with advanced tumors. 3 The appropriate treatment of patients with advanced anal cancer and HIV infection is uncertain. 4 Concomitant radiation therapy and chemotherapy (fluorouracil and mitomycin-C) is the current standard of care for HIV-negative patients with invasive anal carcinoma, and that approach has been investigated and applied successfully in HIV-positive patients with similar anal cancers, particularly those with CD4ϩ T-lymphocyte counts greater than 200 cells/L. 5,6 HIV-positive patients with anal cancer treated with HAART tend to fare better than those patients who are not receiving HAART. 7 It is prudent to point out that our patient never had an anal Papanicolaou (Pap) test (Fig 3, high-grade dysplastic squamous cells; ThinPrep, Cytyc Corporation, Marlborough, MA). HIV-associated anal carcinoma appears to mirror cervical carcinoma in unscreened women, presenting late in the course of the disease and having a protracted, ultimately fatal, course. 8 Screening of HIV-positive patients for anorectal dysplasia and/or malignancy by means of an anal Pap test could save lives. 9