Cell cycle
kinase inhibitors have advanced into clinical trials in oncology. One such molecule,
JNJ-7706621, is a broad-spectrum inhibitor of the
cyclin-dependent kinases and
Aurora kinases that mediate G(2)-M arrest and inhibits
tumor growth in xenograft models. To determine the putative mechanisms of resistance to
JNJ-7706621 that might be encountered in the clinic, the human epithelial cervical
carcinoma cell line (HeLa) was exposed to incrementally increasing concentrations of
JNJ-7706621. The resulting resistant cell population, designated HeLa-6621, was 16-fold resistant to
JNJ-7706621, cross-resistant to
mitoxantrone (15-fold) and
topotecan (6-fold), and exhibited reduced intracellular
drug accumulation of
JNJ-7706621. ABCG2 was highly overexpressed at both the
mRNA ( approximately 163-fold) and
protein levels. The functional role of ABCG2 in mediating resistance to
JNJ-7706621 was consistent with the following findings: (a) an ABCG2 inhibitor,
fumitremorgin C, restored the sensitivity of HeLa-6621 cells to
JNJ-7706621 and to
mitoxantrone; (b) human embryonic kidney-293 cells transfected with ABCG2 were resistant to both
JNJ-7706621 and
mitoxantrone; and (c) resistant cells that were removed from the
drug for 12 weeks and reverted to susceptibility to
JNJ-7706621 showed near-normal ABCG2
RNA levels. ABCG2 is likely to limit the bioavailability of
JNJ-7706621 because
oral administration of
JNJ-7706621 to Bcrp (the murine homologue of ABCG2) knockout mice resulted in an increase in the plasma concentration of
JNJ-7706621 compared with wild-type mice. These findings indicate that ABCG2 mediates the resistance to
JNJ-7706621 and alters the absorption of the compound following administration.