Modulating the function of ATP-binding cassette subfamily G member 2 (ABCG2) with inhibitor cabozantinib

Abstract

Cabozantinib (XL184) is a small molecule tyrosine kinase receptor inhibitor, which targets c-Met and VEGFR2. Cabozantinib has been approved by the Food and Drug Administration to treat advanced medullary thyroid cancer and renal cell carcinoma. In the present study, we evaluated the ability of cabozantinib to modulate the function of the ATP-binding cassette subfamily G member 2 (ABCG2) by sensitizing cells that are resistant to ABCG2 substrate antineoplastic drugs. We used a drug-selected resistant cell line H460/MX20 and three ABCG2 stable transfected cell lines ABCG2-482-R2, ABCG2-482-G2, and ABCG2-482-T7, which overexpress ABCG2. Cabozantinib, at non-toxic concentrations (3 or 5 μM), sensitized the ABCG2-overexpressing cells to mitoxantrone, SN-38, and topotecan. Our results indicate that cabozantinib reverses ABCG2-mediated multidrug resistance by antagonizing the drug efflux function of the ABCG2 transporter instead of downregulating its expression. The molecular docking analysis indicates that cabozantinib binds to the drug-binding site of the ABCG2 transporter. Overall, our findings demonstrate that cabozantinib inhibits the ABCG2 transporter function and consequently enhances the effect of the antineoplastic agents that are substrates of ABCG2. Cabozantinib may be a useful agent in anticancer treatment regimens for patients who are resistant to ABCG2 substrate drugs.

CM082 Enhances the Efficacy of Chemotherapeutic Drugs by Inhibiting the Drug Efflux Function of ABCG2

“…Increasing evidence has shown that the chemotherapeutic outcomes might be promoted by TKIs via inhibiting the activity of ABC transporters. [15][16][17][18] As an oral TKI with multiple targets, CM082 is derived from sunitinib and can suppress angiogenesis by inactivating the pathways of platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), c-Kit, and Fms-like tyrosine kinase 3 (FLT3). A phase I clinical trial of CM082 has been completed in the United States to treat patients with age-related macular degeneration, 19 and a phase IIB trial (ClinicalTrials.gov: NCT02348359) of CM082 is underway.…”

M3814, a DNA-PK Inhibitor, Modulates ABCG2-Mediated Multidrug Resistance in Lung Cancer Cells

“…Another possibility is that some substrate inhibitors can interact with ABCG2 on sites other than the substrate-binding sites and cause conformational changes in the binding pocket which allosterically affect the transportation of some substrates (59). It should be noted that, although several ABCG2 inhibitors were identified as substrates through ATPase assay, overexpression of ABCG2 does not necessarily confer drug resistance to these inhibitors (49,54,(60)(61)(62). Hitherto, the detailed mechanism of this inhibitory effect remained inconclusive and desire further exploration.…”

Repurposing Tyrosine Kinase Inhibitors to Overcome Multidrug Resistance in Cancer: A Focus on Transporters and Lysosomal Sequestration

“…Similarly to their interaction with protein tyrosine kinases, TKIs block the ATP-binding sites of membrane transporters, preventing the phosphorylation and inhibiting the efflux function of transporters [13][14][15][16][17]. Although cabozantinib affected the ATPase activity of the ABCG2 transporter, it also interacted with the transporter at the drug-substrate binding site, antagonizing the transporter by competitive inhibition [15]. TKIs usually inhibit ABC transporters directly and do not alter their expression or localization [13,16,17].…”

“…In vitro studies demonstrated that TKI administration increased intracellular accumulation of rhodamine 123 or doxorubicin in multidrug-resistant cells overexpressing selected ABC transporters [20,21]. Treatment with TKIs inhibiting these transporters (Table 1) was able to enhance the cytotoxicity of substrate drugs, such as paclitaxel, docetaxel [14], vincristine, vinblastine [20,22], doxorubicin [20], etoposide [23], cytarabine [24], mitoxantrone and topotecan [15,19,25], while sensitivity to cisplatin, which is not a substrate for ABC transporters, was not significantly altered [26]. The inhibitory effect of TKIs (e.g., gefitinib or ibrutinib) was comparable to that of known inhibitors of ABC transporters [14,27].…”

“…(BRCP) brigatinib [9]; gefitinib [58] axitinib [34]; cabozantinib [15]; canertinib * [31]; ceritinib [38]; erlotinib [34]; icotinib * [59]; linsitinib * [13]; masitinib * [60]; osimertinib [40]; quizartinib * [61]; regorafenib [34]; sorafenib [24]; sunitinib [21]; tandutinib * [15]; vandetanib [42]; vatalanib * [43] afatinib [32]; alectinib [33]; apatinib * [17]; bosutinib [45]; dasatinib [45]; imatinib [46]; lapatinib [47]; nilotinib [45]; pazopanib [31,34]; ponatinib [19]; telatinib * [25] * experimental TKIs.…”