We have recently reported that there is a significant
Raf-1 kinase dependency of
paclitaxel resistance in human cervical tumor cell lines. In light of the possibility that
Raf-1 kinase inhibitors could be used to enhance
paclitaxel responsiveness in
ovarian cancer, we have characterized the
Raf-1 kinase dependency of
paclitaxel resistance in
ovarian cancer cells. The relationship between
Raf-1 kinase activity and the sensitivity to clinically relevant
paclitaxel concentrations was determined in four
ovarian cancer cell lines (CA-OV3, SK-OV3, 2780/WT and OAW42/WT). Furthermore, in recognition that such a
drug combination would initially be used in patients whose
tumors have recurred following
cisplatin/
paclitaxel treatment, we also determined the
Raf-1 kinase dependency of
paclitaxel cytotoxicity in
cisplatin resistant variants of two of the ovarian cell lines (2780/CP and OAW42/CP). In the two cell lines (2780/WT and OAW42/WT) that possess a wild-type TP53 (TP53wt), the relationship between
Raf-1 kinase activity and
paclitaxel resistance was different from that observed in the cervical tumor cell lines. In these cell lines,
paclitaxel-induced far more cell killing than would have been predicted from their
Raf-1 kinase activity. However, in the
ovarian cancer cell lines (CA-OV3, SK-OV3, 2780/CP and OAW42/CP) that have a mutant TP53 (TP53mut), the cytotoxicity induced by 60 nM
paclitaxel exhibited the same relationship to
Raf-1 kinase activity as previously observed in cervical tumor cell lines. These data suggest that the therapeutic efficacy of
paclitaxel in
ovarian cancer patient whose
tumors have TP53mut might be increased if it is administered in combination with
Raf-1 kinase inhibitors, e.g.,
ISIS 5132.