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Overexpression of ABCB1 Associated With the Resistance to the KRAS-G12C Specific Inhibitor ARS-1620 in Cancer Cells

Xing-Duo Dong1, Meng Zhang2, Chao-Yun Cai1

  • 1Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States.

Frontiers in Pharmacology
|March 14, 2022
PubMed

Insights

The KRAS-G12C inhibitor ARS-1620 is a substrate for ABCB1 (P-glycoprotein), a transporter linked to multidrug resistance. This interaction may influence ARS-1620 efficacy in cancer therapy.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • KRAS-G12C mutations drive cancer, and inhibitors like ARS-1620 target these mutations.
  • ATP-binding cassette super-family B member 1 (ABCB1/P-gp) overexpression is a key mechanism of multidrug resistance (MDR).
  • The relationship between KRAS inhibitors and ABC transporter function, particularly ABCB1, remains under-investigated.

Purpose of the Study:

  • To investigate the potential drug resistance mechanism of ARS-1620 related to ABCB1.
  • To determine if ARS-1620 interacts with and is transported by ABCB1.
  • To assess the implications of ARS-1620's interaction with ABCB1 for cancer therapy.

Main Methods:

  • Cell viability assays in ABCB1-overexpressing and transfected cancer cells.
  • Co-treatment with ARS-1620 and an ABCB1 reversal agent.
  • [3H]-paclitaxel accumulation assays to assess competitive efflux.
  • ATPase activity assays for ABCB1.
  • High-performance liquid chromatography (HPLC) drug accumulation assays.
  • Computer molecular docking analysis.

Main Results:

  • ARS-1620's desensitization effect was enhanced in ABCB1-overexpressing cells, and this was reversible with an ABCB1 inhibitor.
  • ARS-1620 was competitively effluxed by ABCB1, stimulated ABCB1 ATPase activity, and was actively transported out of ABCB1-overexpressing cells.
  • Molecular docking indicated strong interaction between ARS-1620 and ABCB1 transporters.

Conclusions:

  • ARS-1620 is identified as a substrate for the ABCB1 transporter.
  • The interaction with ABCB1 suggests a potential mechanism for drug resistance or altered pharmacokinetics of ARS-1620.
  • Clinical strategies for ARS-1620 therapy should consider the impact of ABCB1 expression in cancer cells.
Keywords:
ABC transporterABCB1ARS-1620KRAS-G12C inhibitormultidrug resistance

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