Implications of ABCG2 Expression on Irinotecan Treatment of Colorectal Cancer Patients: A Review

Abstract

Background: One of the main chemotherapeutic drugs used on a routine basis in patients with metastatic colorectal cancer ((m)CRC) is the topoisomerase-1 inhibitor, irinotecan. However, its usefulness is limited by the pre-existing or inevitable development of resistance. The ATP-binding cassette (ABC) transporter ABCG2/breast cancer resistance protein (BRCP) through its function in xenobiotic clearance might play an important role in irinotecan resistance. With a goal to evaluate the clinical significance of ABCG2 measurements, we here review the current literature on ABCG2 in relation to irinotecan treatment in CRC patients. Results: Few studies have evaluated the association between ABCG2 gene or protein expression and prognosis in CRC patients. Discordant results were reported. The discrepancies might be explained by the use of different criteria for interpretation of results in the immunohistochemistry studies. Only one large study evaluated the ABCG2 protein expression and efficacy of irinotecan in mCRC (CAIRO study, n = 566). This study failed to demonstrate any correlation between ABCG2 protein expression in the primary tumor and response to irinotecan-based treatment. We recently raised questions on how to evaluate ABCG2 immunoreactivity patterns, and the results in the CAIRO study might be influenced by using a different scoring protocol than the one proposed by us. In contrast, our recent exploratory study of ABCG2 mRNA expression in 580 patients with stage III primary CRC (subgroup from the randomized PETACC-3 study) indicated that high ABCG2 tumor tissue mRNA expression might be predictive for lack of efficacy of irinotecan. Conclusion: The biological role of ABCG2 in predicting clinical irinotecan sensitivity/resistance in CRC is uncertain. In particular, the significance of ABCG2 cellular localization needs to be established. Data concerning ABCG2 mRNA expression and prediction of adjuvant irinotecan efficacy are still sparse and need to be confirmed.

An Explorative Analysis of ABCG2/TOP-1 mRNA Expression as a Biomarker Test for FOLFIRI Treatment in Stage III Colon Cancer Patients: Results from Retrospective Analyses of the PETACC-3 Trial

“…An interesting point is that the function of ABCG2 can be inhibited in patients [11]. In Scandion Oncology, we develop novel drugs to inhibit ABCG2 [12,13].…”

Drug resistance and new therapies in colorectal cancer

“…Carboxylesterases (CES), uridine diphosphate glucuronosyltransferase (UGT), hepatic cytochrome P-450 enzymes CYP3A, β-glucuronidase and ATP-binding cassette (ABC) transporter protein are involved in the uptake and metabolism of irinotecan. Consequently, they stand out as major players that determine drug resistance[ 16 , 17 ]. Additionally, targeting the MAPK signal transduction pathway via the inhibition of FGF2, FGF9, MECOM, PLA2G4C and PRKACB could also potentially improve responsiveness to irinotecan[ 18 ].…”

Wechselwirkungen zwischen bioaktiven Sekundärmetaboliten und Irinotecan

“…Hinsichtlich der Ausbildung einer Irinotecan-Resistenzentwicklung könnte auch das Transportprotein MXR(BCRP) (ABCG2) eine Bedeutung haben. Eine aktuelle Studie weist diesbezüglich auf die Notwendigkeit weiterer Untersuchungen hin [30]. Für Quercetin wurde im Rahmen einer In-vitro-Untersuchung eine inhibitorische Wirkung auf den ABC-Transporter MXR(BCRP) (ABCG2) festgestellt [31].…”