BMS-345541 + Dasatinib Resensitizes Carboplatin-Resistant, Recurrent Ovarian Cancer Cells

Johns Hopkins medical researchers discovered through proteomic analysis that RELA and STAT5 are upregulated in carboplatin resistant ovarian cancer cells, according to a published study appearing in the June 18 edition of PLoS One. Moreover, the researchers also demonstrated that BMS-345541 (a NF-kappaB inhibitor) and dasatinib (a STAT5 inhibitor) could resensitize carboplatin-resistant, recurrent ovarian cancer cells.

Although most ovarian cancer patients are initially responsive to platinum-based chemotherapy, almost all develop recurrent chemoresistant tumors. For this reason, Johns Hopkins researchers set out to determine the scientific underpinnings of carboplatin drug resistance in ovarian cancer cells. The researchers compared the proteomes of paired primary and recurrent post-chemotherapy, high grade serous ovarian carcinomas from nine ovarian cancer patients.

As compared to the primary tumors, more than one-half of the recurrent tumors expressed higher levels of several proteins including:  CP, FN1, SYK, CD97, AIF1, WNK1, SERPINA3, APOD, URP2, STAT5B and RELA (NF-kappaB p65).  A short hairpin RNA (shRNA) is a sequence of RNA that makes a tight hairpin turn which can be used to silence gene expression through so-called “RNA interference.” Based on shRNA screening for the upregulated genes in in vitro carboplatin-resistant ovarian cancer cells, the researchers determined that simultaneous silencing of RELA and STAT5B was the most effective way to resensitize tumor cells for carboplatin treatment.

In an attempt to recreate the same results achieved with gene silencing through therapeutic drug use, the researchers used BMS-345541 (a NF-kappaB inhibitor) and dasatinib (Sprycel®)(a STAT5 inhibitor)  to significantly enhance cell sensitivity to carboplatin. The researchers also discovered that expression of RELA and STAT5B enhanced Bcl-xL promoter activity; however, treatment with BMS-345541 and dasatinib decreased such activity.

Accordingly, the researchers concluded that proteomic analysis identified RELA and STAT5 as two major proteins associated with carboplatin resistance in recurrent ovarian cancer tumors. Furthermore, the study results reveal that NF-kappaB and STAT5 inhibitors could resensitize carboplatin-resistant, recurrent ovarian cancer cells, thereby suggesting that these inhibitor drugs can be used to benefit select ovarian cancer patients.

Source: Jinawath N, Vasoontara C, Jinawath A, et. al.  Oncoproteomic analysis reveals co-upregulation of RELA and STAT5 in carboplatin resistant ovarian carcinoma. PLoS One. 2010 Jun 18;5(6):e11198.