Overexpression of ATP-binding cassette transporter ABCG2 as a potential mechanism of acquired resistance to vemurafenib in BRAF(V600E) mutant cancer cells

Abstract

Melanoma is the most serious type of skin cancer with a high potential for metastasis and very low survival rates. The discovery of constitutive activation of the BRAF kinase caused by activating BRAF(V600E) kinase mutation in most melanoma patients led to the discovery of the first potent BRAF(V600E) signaling inhibitor, vemurafenib. Vemurafenib was effective in treating advanced melanoma patients and was proposed for the treatment of other BRAF(V600E) mutant cancers as well. Unfortunately, the success of vemurafenib was hampered by the rapid development of acquired resistance in different types of BRAF(V600E) mutant cancer cells. It becomes important to identify and evaluate all of the potential mechanisms of cellular resistance to vemurafenib. In this study, we characterized the interactions of vemurafenib with three major ATP-binding cassette (ABC) transporters, ABCB1, ABCC1 and ABCG2. We found that vemurafenib stimulated the ATPase activity and potently inhibited drug efflux mediated by ABCB1 and ABCG2. Vemurafenib also restored drug sensitivity in ABCG2-overexpressing cells. Moreover, we revealed that in the presence of functional ABCG2, BRAF kinase inhibition by vemurafenib is reduced in BRAF(V600E) mutant A375 cells. Taken together, our findings indicate that ABCG2 confers resistance to vemurafenib in A375 cells, suggesting involvement of this transporter in acquired resistance to vemurafenib. Thus, combination chemotherapy targeting multiple pathways could be an effective therapeutic strategy to overcome acquired resistance to vemurafenib for cancers harboring the BRAF(V600E) mutation.

Epithelial–Mesenchymal Transition Predicts Polo-Like Kinase 1 Inhibitor–Mediated Apoptosis in Non–Small Cell Lung Cancer

“…We tested several potential biomarkers that were previously demonstrated to correlate with cancer cell line sensitivity to PLK1 inhibition, including PLK1 expression, TP53 mutation (6, 8), chromosomal instability (8), and ABCB1 or ABCG2 overexpression (46). Our findings were consistent with low rates of response of NSCLC to treatment with PLK1 inhibitors in clinical trials despite a high prevalence of PLK1 overexpression in tumors (3, 4, 21).…”

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

“…All HEK293 and HEK293 transfected lines were maintained in 2 mg/mL G418 [29]; MCF7-FLV1000 cells were cultured in the presence of 1 μg/mL flavopiridol [31, 32], whereas 1 μg/μL vinblastine was added to KB-V-1 cells [33]. CORL-23/P, CORL-23/R, S1 and S1-M1-80 cells were cultured in RPMI-1640 (Gibco, Invitrogen, CA, USA), supplemented with 10 % FCS, 2 mM L-glutamine and 100 units of penicillin/streptomycin/mL at 37 °C in 5 % CO 2 humidified air.…”

“…CORL-23/P, CORL-23/R, S1 and S1-M1-80 cells were cultured in RPMI-1640 (Gibco, Invitrogen, CA, USA), supplemented with 10 % FCS, 2 mM L-glutamine and 100 units of penicillin/streptomycin/mL at 37 °C in 5 % CO 2 humidified air. The CORL-23/R cells were maintained in the presence of 0.2 μg/mL of doxorubicin, whereas S1-M1-80 cells were cultured in 80 μM of mitoxantrone as described previously [29]. NIH3T3-G185 cells were maintained in the presence of 60 ng/mL colchicine [34].…”

The phototoxicity of vemurafenib: An investigation of clinical monochromator phototesting and in vitro phototoxicity testing

“…In addition to PpIX, ABCG2 has been reported to transport a wide variety of agents including some fluoroquinolones, and VNIB [15]. A large number of inhibitors of ABCG2 activity have also been described [16], including VNIB, which was able to reverse resistance to chemotherapeutic agents in ABCG2 overexpressing cell lines [17].…”