Human ABCB1 (P-glycoprotein) and ABCG2 mediate resistance to BI 2536, a potent and selective inhibitor of Polo-like kinase 1

Abstract

The overexpression of the serine/threonine specific polo-like kinase 1 (Plk1) has been detected in various types of cancer, and thus has fast become an attractive therapeutic target for cancer therapy. BI 2536 is the first selective inhibitor of Plk1 that inhibits cancer cell proliferation by promoting G2/M cell cycle arrest at nanomolar concentrations. Unfortunately, alike most chemotherapeutic agents, the development of acquired resistance to BI 2536 is prone to present a significant therapeutic challenge. One of the most common mechanisms for acquired resistance in cancer chemotherapy is associated with the overexpression of ATP-binding cassette (ABC) transporters ABCB1, ABCC1 and ABCG2. Here, we discovered that overexpressing of either ABCB1 or ABCG2 is a novel mechanism of acquired resistance to BI 2536 in human cancer cells. Moreover, BI 2536 stimulates the ATPase activity of both ABCB1 and ABCG2 in a concentration-dependent manner, and inhibits the drug substrate transport mediated by these transporters. More significantly, the reduced chemosensitivity and BI 2536-mediated G2/M cell cycle arrest in cancer cells overexpressing either ABCB1 or ABCG2 can be significantly restored in the presence of selective inhibitor or other chemotherapeutic agents that also interact with ABCB1 and ABCG2, such as tyrosine kinase inhibitors nilotinib and lapatinib. Taken together, our findings indicate that in order to circumvent ABCB1 or ABCG2-mediated acquired resistance to BI 2536, a combined regimen of BI 2536 and inhibitors or clinically active drugs that potently inhibit the function of ABC drug transporters, should be considered as a potential treatment strategy in the clinic.

Plk1 Inhibitors in Cancer Therapy: From Laboratory to Clinics

“…However, the antitumor activity of GSK461364 is shown to be reduced when ABCB1 is overexpressed. Like the results found in vitro , re-sensitization to GSK461364 occurs when ABCB1 is inhibited (91). …”

“…The recommended dose for phase II was found to be 225 mg in a group 1 schedule, in combination with an anticoagulant to counteract adverse effects of the inhibitor treatment (90). GSK461364 has also been found to inhibit ABCB1-mediated calcein-AM outflow (91). However, the antitumor activity of GSK461364 is shown to be reduced when ABCB1 is overexpressed.…”

BI 6727 and GSK461364 suppress growth and radiosensitize osteosarcoma cells, but show limited cytotoxic effects when combined with conventional treatments

“…This kinase plays an essential role during cell division [4], and its interference by shRNA [2,5] or the small ATP-competitive inhibitor BI 2536 [6,7] has been shown to promote mitotic arrest and cell death in OS cells, pointing to PLK1 as a pertinent therapeutic target. However, the highly promising preclinical data obtained in the last decade with BI 2536 have several limitations such as low intratumor levels [8], acquired resistance [9], and drug-related adverse events in clinical trials [10].…”

Effect of AKT3 expression on MYC‐ and caspase‐8‐dependent apoptosis caused by polo‐like kinase inhibitors in HCT 116 cells

“…Various mechanisms, such as the increased expression of drug efflux transporters, the alteration of target molecules, the upregulation of survival signals, and the downregulation of cell death mechanisms, have been investigated . The overexpression of P‐glycoprotein (P‐GP) is one of the commonest resistance mechanisms to BI 2536, BI 6727, and GSK461364, which are investigated in this study . A PLK1 gene mutation has also been reported to confer resistance to BI 2536 …”

“…(15) The overexpression of P-glycoprotein (P-GP) is one of the commonest resistance mechanisms to BI 2536, BI 6727, and GSK461364, which are investigated in this study. (16)(17)(18) A PLK1 gene mutation has also been reported to confer resistance to BI 2536. (19) In this study, we established five BI 2536-resistant cell lines (BI 10-1-5, BI 10-1-10, BI 20-1, BI 40-1, and BI 40-2) from human colorectal cancer HCT 116 cells, to investigate the mechanisms responsible for the sensitivity to PLKis.…”