Lost in translation: Revisiting the use of tyrosine kinase inhibitors in colorectal cancer

Iyer, Kirti K.; Erp, Nielka P. van; Tauriello, Daniele V.F.; Verheul, H.; Poel, Dennis

doi:10.1016/j.ctrv.2022.102466

Cited by 6 publications

(6 citation statements)

References 115 publications

(102 reference statements)

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“…Cell lines remain a widely used model to test TKIs in mCRC [12]. Due to their inability to re ect mCRC heterogeneity, plastic-adapted (2D) cell lines have serious limitations [19,20].…”

Section: Discussionmentioning

confidence: 99%

“…Although organoids are increasingly used in both fundamental and translational research, their potential as the preferred modality for (pre-) clinical e cacy and pharmacological research remains only partially explored. Besides the advances made in the current work, these models could be further improved with the addition of components from the tumour microenvironment (TME) to study drug distribution, but also because the TME can be a signi cant determinant in therapeutic response [24,25] or can harbour relevant targets itself [12,26,27].…”

Section: Discussionmentioning

confidence: 99%

“…Another important barrier is the challenge of translating preclinical drug concentrations to patient dosing; to determine and implement the required exposure for e cacy in the clinic. Indeed, as sparse as reliable clinical data on intra-tumoral drug levels are, preclinical studies rarely assess effective intracellular drug exposure [12]. Therefore, our pharmacological evaluations in TKI-treated PDTOs are pertinent in providing unprecedented insight in the relation between activity and resistance based on intra-cellular drug concentrations.…”

Section: Discussionmentioning

confidence: 99%

“…Over 40 Food and Drug Administration (FDA) approved TKIs have shown promising anticancer activity in preclinical CRC studies. Yet, despite several clinical trials, only regorafenib has been FDA approved as monotherapy for the treatment of mCRC [12]. This huge translational failure could be attributed to the lack of models mimicking complex tumour behaviour, leading to overestimation of preclinical drug e cacy, or to the neglect of the drug exposure levels that are required for anticancer e cacy that are not reached in the clinic by using standard dosing.…”

Section: Introductionmentioning

confidence: 99%

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

Iyer¹,

Poel²,

Miggelenbrink³

et al. 2023

Preprint

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Background Despite major interest in tyrosine kinase inhibitors (TKIs) as a treatment option for metastatic colorectal cancer (mCRC), almost all TKIs tested for mCRC fail in early-phase clinical trials. Although showing specific target inhibition at low concentrations, TKIs have a much broader kinase inhibitory potency at higher concentrations. In an attempt to leverage these many additional, low-affinity targets, high-dose regimens that may trigger efficacy are explored. Here, we studied unprecedented drug exposure–response relationships in vitro using mCRC patient-derived tumour organoids (PDTOs). Methods We established patient-derived tumor organoids (PDTOs) from mCRC biopsies and, based on favorable physicochemical and pharmacokinetic properties, selected 3 TKIs (sunitinib, cediranib and osimertinib). Following standard IC50 assessment using continuous dosing with a concentration range, we investigated the cytotoxic antitumor effect of high-dose, short-term (HDST) treatment. Five PDTOs were exposed to 20 µM TKI for 1–24h, washed and given normal medium, and PDTO-outgrowth was determined 1 week later. At exposures of 1, 3 and 6 h, we measured intra-tumoroid TKI concentrations using a clinically validated LC/MS-MS method. PDTO cell death was observed using live-cell microscopy, and quantified by both caspase 3/7 enzyme activity assay and cleaved caspase-3 immunofluorescent staining. Results We show that most PDTOs tested are sensitive to multikinase TKIs sunitinib and cediranib, and all to osimertinib. Furthermore, we demonstrate that high-dose, short-term(HDST) TKI treatment effectively blocks organoid growth. In line with recent clinical data of high-dose sunitinib tumour accumulation, HDST treatment led to markedly elevated intra-tumoroid TKI concentrations, which correlated with PDTO sensitivity. This suggests exposure-dependent cytotoxicity and supports the concept that efficacy is induced by a broad kinase inhibitory spectrum. Mechanistically, HDST osimertinib treatment for just 3 hours induced regulated cell death in treated organoids. Conclusion Our work provides a better understanding of TKI exposure vs response and can be used to determine patient-specific sensitivity. In addition, 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.

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“…Cell lines remain a widely used model to test TKIs in mCRC [12]. Due to their inability to re ect mCRC heterogeneity, plastic-adapted (2D) cell lines have serious limitations [19,20].…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Iyer¹,

Poel²,

Miggelenbrink³

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…focused on signalling targets controlled by protein tyrosine kinases to emphasize the potential of kinase inhibitors as treatment agents for metastatic CRC (mCRC). Over 50 tyrosine kinase inhibitors (TKIs) have been approved by the U.S. Food and Drug Administration ( 3 ). However, around 42 TKIs demonstrating preclinical antitumour activity, and despite numerous clinical trials, only regorafenib has been approved for clinical use in mCRC.…”

Section: New Therapeutic Strategiesmentioning

confidence: 99%