2. Academic Validation
  3. Elacridar improves sunitinib efficacy in colorectal cancer models

Elacridar improves sunitinib efficacy in colorectal cancer models

  • Eur J Pharm Sci. 2025 Sep 1:212:107194. doi: 10.1016/j.ejps.2025.107194.
Dennis Poel 1,  Kirti K Iyer 2,  Bob van Gasteren 3,  Beau B C Dagniaux 3,  Erik van den Hombergh 4,  Daniele V F Tauriello 5,  Henk M W Verheul 6,  Nielka P van Erp 4
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, the Netherlands; Department of Medical Biosciences, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, the Netherlands. Electronic address: d.poel1@amsterdamumc.nl.
  • 2 Department of Medical Oncology, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, the Netherlands; Department of Medical Biosciences, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, the Netherlands.
  • 3 Department of Medical Biosciences, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, the Netherlands.
  • 4 Department of Pharmacy, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, the Netherlands.
  • 5 Department of Medical Biosciences, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, the Netherlands; Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Centre Rotterdam, the Netherlands.
  • 6 Department of Medical Oncology, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, the Netherlands; Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Centre Rotterdam, the Netherlands.
PMID: 40639493 DOI: 10.1016/j.ejps.2025.107194
Abstract

To improve treatment outcome for unresectable metastatic colorectal Cancer (mCRC), many small molecule kinase inhibitors (KIs) have been tested. Most fail in early-phase clinical trials due to intrinsic resistance. As ATP Binding Cassette transporters are known to cause treatment resistance in mCRC, as well as to obtain higher intracellular drug concentrations, we evaluated whether inhibition of these transporters could potentiate KI efficacy. In patient-derived tumour organoids (PDTOs) from mCRC biopsies, preincubation with potent transporter inhibitor elacridar significantly improved sunitinib efficacy. Contrasting expectations, this was accompanied by reduced intracellular sunitinib accumulation. Mechanistically, confocal fluorescence imaging revealed reduced lysosomal sequestration of sunitinib in cells preincubated with elacridar. Storage of drugs-that are lysosomotropic and substrates of ABC-transporters-in subcellular compartments reduces the active pool and potentially contributes to intrinsic drug resistance in mCRC. Combination strategies that target ABC-transporters or lysosomes might be considered to potentiate drug efficacy.

Keywords

ABC-transporters; Kinase inhibitors; Metastatic colorectal cancer; Patient-derived tumour organoids; Preclinical pharmacokinetics.

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