Multidrug and regulation of multidrug resistance
The Sikic laboratory has made significant contributions to understanding the biology and clinical significance of multidrug resistance (MDR), particularly the P-glycoprotein (P-gp) multidrug transporter and regulation of the ABCB1 gene. He discovered that deletion of aa335 changes the drug-binding spectrum and is integral to the pharmacophore of P-gp. He also defined specific sites of transactivation of ABCB1, and mechanisms of amplification of the gene.
Clinical trials of modulation of multidrug resistance
The laboratory work on drug resistance mechanisms led to a series of clinical Phase I-III trials that defined this field. Early on, Sikic’s group found that P-gp inhibition resulted in significant pharmacokinetic alterations of several anticancer drugs, with the potential for markedly increased toxicities unless doses were adjusted. These findings, and the co-existence of other resistance mechanisms in human cancers, redefined the field and demonstrated the limited clinical utility of MDR modulation.
Taxane Mechanisms of Resistance
The taxanes are widely used as chemotherapy agents and have substantial clinical activity in breast, ovarian, lung, and other cancers. Despite activity in human tumors, development of drug resistance presents a serious clinical problem.
Our objective was to study mechanisms of cellular resistance to taxanes, paclitaxel (Taxol) and docetaxel (Taxotere), and the second generation taxane, cabazitaxel (Jevtana) which was approved for the treatment of hormone-refractory metastatic prostate cancer. Although the major known mechanism of resistance to these agents is multidrug resistance mediated by ABCB1, we hypothesize that the relative expression and composition of tubulin isoforms, the binding targets for these drugs, will differ in resistant cell lines which may alter drug sensitivity.
We established cellular models of taxane resistance in ovarian and breast cancer cell lines to further study the mechanisms of resistance to this important class of drugs, to explore approaches to overcome drug resistance, and to identify biomarkers for predicting sensitivity or resistance in the clinical setting.
Lacayo NJ, Duran GE, Sikic BI. Modulation of resistance to idarubicin by the cyclosporin PSC 833 (valspodar) in multidrug-resistant cells. J Exp Ther Oncol 3(3):127-35, 2003.
Chen G, Duran GE, Steger KA, Lacayo NJ, Jaffrézou JP, Dumontet C, Sikic BI. Multidrug-resistant human sarcoma cells with a mutant P-glycoprotein, altered phenotype, and resistance to cyclosporins. J Biol Chem 272(9): 5974-82, 1997.
Schaner ME, Ross DT, Ciaravino G, Sorlie T, Troyanskaya O, Diehn M, Wang YC, Duran GE, Sikic TL, Caldeira S, Skomedal H, Tu IP, Hernandez-Boussard T, Johnson SW, O'Dwyer PJ, Fero MJ, Kristensen GB, Borresen-Dale AL, Hastie T, Tibshirani R, van de Rijn M, Teng NN, Longacre TA, Botstein D, Brown PO, Sikic BI. Gene Expression patterns in ovarian carcinomas. Mol Biol Cell 14(11): 4376-86, 2003.
The Sikic group utilized gene expression profiling and systems biology to yield insight into cancer taxonomy and prognostic and predictive signatures for cancer therapies. With their colleagues Olivier Gevaert and Sylvia Plevritis, they have identified driver genes for ovarian cancers.