In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 4364-4364
Abstract:
Ovarian clear cell carcinoma (OCCC) is a subtype of epithelial ovarian cancer and accounts for 5-25% of ovarian cancers. OCCC has shown higher resistance to first-line platinum and taxane-based chemotherapy, resulting in worse prognosis. Most common mutations occur in the genes ARID1A (46%) and PIK3CA (33%). Using array comparative genomic hybridization (aCGH), we previously identified frequent chromosomal gain at 8q24, which includes the encoding sequence for focal-adhesion kinase (FAK)/Protein Tyrosine Kinase 2 (PTK2), a protein that provides signaling and scaffolding functions at sites of integrin adhesion. To validate the copy number gain of PTK2 and correlate the copy number variations with PIK3CA mutations, we analyzed the copy number gain and protein expression levels of PTK2, and examined the PIK3CA mutations in 67 OCCC samples. We found that PTK2 copy number gain and loss were at a frequency of 23% and 25%, respectively. PTK2 gain significantly correlated with the strong expression of PTK2. PIK3CA mutations were found in 20% of the samples. About 40% of the tested samples showed PTK2 gain or PIK3CA mutation. PIK3CA mutations are not strictly mutually exclusive to PTK2 gain, but are more likely to occur in samples with PTK2 copy number normal or loss. Genetic alterations in OCCC mainly activate the PTK2/PI3K/AKT signaling pathway, which makes the pathway an attractive candidate for targeted therapeutics. We, therefore, treated OVMANA, OVISE and OVTOKO OCCC cell lines with PTK2 inhibitors (PF-562271 or PF-573228), or a combination of PF-562271 with a PI3K/mTOR dual inhibitor (BEZ235). Copy number variations of PTK2 were not related to the drug sensitivity of the OCCC cell lines. Drug sensitivity of most of the cells was enhanced toward PF-562271 than PF-573228. OVMANA cells with PIK3CA mutations were more sensitive to a combination of PI3K/mTOR and PTK2 inhibitor than the cells without PIK3CA mutations. Our findings thus suggest that the PTK2/PI3K/AKT signaling pathway is frequently activated in OCCC, and a combination of inhibitor drugs would prove to be necessary to enhance the overall drug efficacy in treating OCCC. Citation Format: Heejei Yoon, Yoon-La Choi, Ji-Young Song, Ingu Do, So Young Kang, Young-Hyeh Ko, Sangyong Song, Byong-Gie Kim. Copy number gain of PTK2 and PIK3CA mutations are common genetic alterations in ovarian clear cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4364. doi:10.1158/1538-7445.AM2013-4364
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2013-4364
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2013
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
Bookmarklink