Inhibition of the transmembrane transporter ABCB1 overcomes resistance to doxorubicin in patient-derived organoid models of HCC

  • Hepatol Commun. 2024 May 2;8(5):e0437. doi: 10.1097/HC9.0000000000000437.
Lauriane Blukacz  1 ,  Sandro Nuciforo  1 ,  Geoffrey Fucile  2 ,  Fredrik Trulsson  1 ,  Urs Duthaler  3  4 ,  Stefan Wieland  1 ,  Markus H Heim  1  5
Affiliations
  • 1. Department of Biomedicine, Hepatology Laboratory, University and University Hospital Basel, Basel, Switzerland.
  • 2. sciCORE Center for Scientific Computing and Center for Data Analytics, University of Basel, Basel, Switzerland.
  • 3. Department of Biomedicine, Clinical Pharmacology and Toxicology, University and University Hospital Basel, Basel, Switzerland.
  • 4. Department of Pharmaceutical Sciences, Clinical Pharmacology and Toxicology, University of Basel, Basel, Switzerland.
  • 5. University Digestive Health Care Center Basel - Clarunis, Basel, Switzerland.
PMID: 38696353 DOI: 10.1097/HC9.0000000000000437
Abstract

Background: Transarterial chemoembolization is the first-line treatment for intermediate-stage HCC. However, the response rate to transarterial chemoembolization varies, and the molecular mechanisms underlying variable responses are poorly understood. Patient-derived hepatocellular carcinoma organoids (HCCOs) offer a novel platform to investigate the molecular mechanisms underlying doxorubicin resistance.

Methods: We evaluated the effects of hypoxia and doxorubicin on cell viability and cell cycle distribution in 20 patient-derived HCCO lines. The determinants of doxorubicin response were identified by comparing the transcriptomes of sensitive to resistant HCCOs. Candidate genes were validated by pharmacological inhibition.

Results: Hypoxia reduced the proliferation of HCCOs and increased the number of cells in the G0/G1 phase of the cell cycle, while decreasing the number in the S phase. The IC50s of the doxorubicin response varied widely, from 29nM to >1µM. Doxorubicin and hypoxia did not exhibit synergistic effects but were additive in some HCCOs. Doxorubicin reduced the number of cells in the G0/G1 and S phases and increased the number in the G2 phase under both normoxia and hypoxia. Genes related to drug metabolism and export, most notably ABCB1, were differentially expressed between doxorubicin-resistant and doxorubicin-sensitive HCCOs. Small molecule inhibition of ABCB1 increased intracellular doxorubicin levels and decreased drug tolerance in resistant HCCOs.

Conclusions: The inhibitory effects of doxorubicin treatment and hypoxia on HCCO proliferation are variable, suggesting an important role of tumor-cell intrinsic properties in doxorubicin resistance. ABCB1 is a determinant of doxorubicin response in HCCOs. Combination treatment of doxorubicin and ABCB1 inhibition may increase the response rate to transarterial chemoembolization.

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