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Purpose: A significant number of women with serous ovarian cancer are intrinsically refractory to platinum-based treatment. We analyzed somatic DNA copy number variation and gene expression data to identify key mechanisms associated with primary resistance in advanced-stage serous cancers., Experimental Design: Genome-wide copy number variation was measured in 118 ovarian tumors using high-resolution oligonucleotide microarrays. A well-defined subset of 85 advanced-stage serous tumors was then used to relate copy number variation to primary resistance to treatment. The discovery-based approach was complemented by quantitative-PCR copy number analysis of 12 candidate genes as independent validation of previously reported associations with clinical outcome. Likely copy number variation targets and tumor molecular subtypes were further characterized by gene expression profiling., Results: Amplification of 19q12, containing cyclin E (CCNE1), and 20q11.22-q13.12, mapping immediately adjacent to the steroid receptor coactivator NCOA3, was significantly associated with poor response to primary treatment. Other genes previously associated with copy number variation and clinical outcome in ovarian cancer were not associated with primary treatment resistance. Chemoresistant tumors with high CCNE1 copy number and protein expression were associated with increased cellular proliferation but so too was a subset of treatment-responsive patients, suggesting a cell-cycle independent role for CCNE1 in modulating chemoresponse. Patients with a poor clinical outcome without CCNE1 amplification overexpressed genes involved in extracellular matrix deposition., Conclusions: We have identified two distinct mechanisms of primary treatment failure in serous ovarian cancer, involving CCNE1 amplification and enhanced extracellular matrix deposition. CCNE1 copy number is validated as a dominant marker of patient outcome in ovarian cancer.

Purpose: The EML4-ALK fusion gene has been detected in approximately 7% 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.