High-dose short-term osimertinib treatment is effective in patient-derived metastatic colorectal cancer organoids

Kirti K Iyer; Dennis Poel; Anne Miggelenbrink; Wouter Kerkhof; Jorien Janssen; Lotte Bakkerus; Loek de Jong; Erik van den Hombergh; Iris D Nagtegaal; Daniele V F Tauriello; Nielka P van Erp; Henk M W Verheul

doi:10.1038/s44276-024-00042-0

High-dose short-term osimertinib treatment is effective in patient-derived metastatic colorectal cancer organoids

BJC Rep. 2024 Apr 3;2(1):29. doi: 10.1038/s44276-024-00042-0.

Authors

Kirti K Iyer^#^{1

2}, Dennis Poel^#^{1

2}, Anne Miggelenbrink^{1

2}, Wouter Kerkhof^{1

2}, Jorien Janssen¹, Lotte Bakkerus¹, Loek de Jong³, Erik van den Hombergh³, Iris D Nagtegaal⁴, Daniele V F Tauriello^{2

5}, Nielka P van Erp³, Henk M W Verheul^{6

7}

Affiliations

¹ Department of Medical Oncology, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands.
² Department of Medical Biosciences, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands.
³ Department of Pharmacy, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands.
⁴ Department of Pathology, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands.
⁵ Department of Medical Oncology, Erasmus Medical Centre, Rotterdam, The Netherlands.
⁶ Department of Medical Oncology, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands. [email protected].
⁷ Department of Medical Oncology, Erasmus Medical Centre, Rotterdam, The Netherlands. [email protected].

^# Contributed equally.

Abstract

Background: Most tyrosine kinase inhibitors (TKIs) have failed in clinical trials for metastatic colorectal cancer (mCRC). To leverage the additional lower-affinity targets that most TKIs have, high-dose regimens that trigger efficacy are explored. Here, we studied unprecedented drug exposure-response relationships in vitro using mCRC patient-derived tumour organoids (PDTOs).

Methods: We investigated the cytotoxic anti-tumour effect of high-dose, short-term (HDST) TKI treatment on 5 PDTOs. Sunitinib, cediranib and osimertinib were selected based on favourable physicochemical and pharmacokinetic properties. Intra-tumoroid TKI concentrations were measured using a clinically validated LC/MS-MS method. Cell death was determined using an enzyme activity assay, immunofluorescent staining and western blotting.

Results: Most PDTOs tested were sensitive to sunitinib and cediranib, but all to osimertinib. Furthermore, HDST osimertinib treatment effectively blocks organoid growth. This treatment led to markedly elevated intra-tumoroid TKI concentrations, which correlated with PDTO sensitivity. Mechanistically, HDST osimertinib treatment induced apoptosis in treated PDTOs.

Conclusion: Our work provides a better understanding of TKI exposure vs response and can be used to determine patient-specific sensitivity. Additionally, these results may guide both mechanistic elucidation in organotypic translational models and the translation of target drug exposure to clinical dosing strategies. Moreover, HDST osimertinib treatment warrants clinical exploration for mCRC.