Reversal of resistance to docetaxel and cabazitaxel in prostate cancer cells with ritonavir

Background: The taxanes docetaxel and cabazitaxel are indicated for treatment of metastatic castration-resistant prostate cancer (mCRPC). Resistance to often develops during treatment, which can be due an increased efflux via P-glycoprotein (P-gp) from the intracellular site action. Ritonavir is inhibitor both cytochrome P4503A4 (CYP3A4) P-gp. In this study we investigated whether ritonavir could improve efficacy through inhibition P-gp in docetaxel-resistant cells. Methods: Prostate cell lines DU-145 22Rv1 were exposed increasing doses generate resistant sublines, DU145-DOC10 22Rv1DOC8 respectively. Gene expression clones was compared that parental lines. treated with several drug combinations 8*2 matrix 3D tumor clonogenic assay. following tested: docetaxel/ritonavir, docetaxel/elacridar cabazitaxel/ritonavir. IC50 values single agent drugs as well combination effects between (using a Bliss independence dose-response evaluation) determined all Results: most differentially upregulated gene ABCB1 (P-gp). Western blotting showed expressed more than A comparison observed has been summarized below table.Table(abstract: 306 (PB086))DU-145DU-145DOC10DU-145DOC1022Rv122Rv1DOC822Rv1DOC8Docetaxel (nM)2.99.52.8*with 10 μM ritonavir,1.354.63.0**with 32 ritonavir.Cabazitaxel (nM)0.61.50.6*with ritonavir,0.79.50.7**with ritonavir.* ritonavir,** ritonavir. Open table new tab We found resistance conferred cross-resistance cabazitaxel. With addition (DU-145DOC10) (22Rv1DOC8) cytoxicity returned level similar experiment specific elacridar concentration 0.3 sufficient reverse same lines, confirming important mechanism-of-action. DU-145-DOC10 cells strong synergistic seen docetaxel/ritonavir cabazitaxel/ritonavir combination, contrast lack synergy these combinations. Conclusions: demonstrated potential or offset (and, by implication its cross-resistance, also cabazitaxel), primarily mediated This provides rationale clinically test patients mCRPC. Conflict interest: Ownership: Jos Beijnen shareholder Modra Pharmaceuticals. Board Directors: Colin Freund Eric van der Putten directors