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Abstract
Methods:
We created novel
A2780-derived ovarian cancer cell lines resistant to paclitaxel and
olaparib following continuous incremental drug selection. MTT assays
were used to assess chemosensitivity to paclitaxel and olaparib in
drug-sensitive and drug-resistant cells±the ABCB1 inhibitors verapamil
and elacridar and cross-resistance to cisplatin, carboplatin,
doxorubicin, rucaparib, veliparib and AZD2461. ABCB1 expression was
assessed by qRT-PCR, copy number, western blotting and
immunohistochemical analysis and ABCB1 activity assessed by the Vybrant
and P-glycoprotein-Glo assays.
Conclusions:
We describe a common
ABCB1-mediated mechanism of paclitaxel and olaparib resistance in
ovarian cancer cells. Optimal choice of PARP inhibitor may therefore
limit the progression of drug-resistant disease, while routine
prescription of first-line paclitaxel may significantly limit subsequent
chemotherapy options in ovarian cancer patients.
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