Eupatilin attenuates vemurafenib resistance through inhibition of ABCB1 in melanoma

The clinical efficacy of vemurafenib in melanoma patients has been hindered by the development of acquired resistance.

To comprehend the molecular signaling pathways underlying this resistance and identify potential strategies to overcome it.

We first constructed the vemurafenib-resistant melanoma cell lines A375R and identified ABCB1 as a potential driver through RNA sequence. ABCB1 knockdown on vemurafenib sensitivity was assessed by CCK-8 and colony formation. FDA-approved eupatilin was identified as a novel ABCB1 inhibitor by employing the quantitative structure-activity relationship model and ADMETlab 2.0. The combined effect of eupatilin and vemurafenib was detected in in vitro and in vivo.

The expression of ABCB1 was upregulated in A375R. The genetic inhibition of ABCB1 could restore sensitivity to vemurafenib in resistant cells. Eupatilin was a previously unexplored compound that can selectively target ABCB1 and exhibit favorable safety profiles. Notably, we identified eupatilin as a therapeutic intervention to counteract acquired resistance to vemurafenib in cell and animal experiments, resulting in the inhibition of tumor growth. Furthermore, we found upregulation of ABCB1 in resistant cells due to the activation of the PI3K-AKT-mTOR pathway.

These findings provided valuable insights into a novel molecular mechanism underlying vemurafenib resistance and highlighted potential ABCB1 as a viable target, in conjunction with its novel inhibitor eupatilin, to enhance effectiveness of vemurafenib.