Lost in translation: Revisiting the use of tyrosine kinase inhibitors in colorectal cancer (2024)

Abstract

Patients with advanced or metastatic colorectal cancer ((m)CRC) have limited effective treatment options resulting in high mortality rates. A better understanding of the molecular basis of this disease has led to growing interest in small molecule tyrosine kinase inhibitors (TKIs) for its treatment. However, of around 42 TKIs demonstrating preclinical anti-tumour activity, and despite numerous clinical trials, only 1 has been approved for clinical use in mCRC. Clearly, there is a huge gap in the translation of these targeted therapies to the clinic. This underlines the limitations of preclinical models to predict clinical drug efficacy and to fully characterize the mechanism of action. Moreover, several relevant topics remain poorly resolved. Do we know the actual intracellular concentrations that are required for anticancer efficacy, and what range of intra-tumoral drug concentrations is reached in clinical setting? Are the intended targeted kinases responsible for the anti-cancer activity or are other unexpected cellular targets involved? Do we have any idea of the effect of these drugs on the tumour microenvironment and does this help explain therapy success, failure or heterogeneity? In this review, we address these questions and discuss concepts that jointly complicate the clinical translation of TKIs for CRC. Finally, we will argue that an integrated approach with more sophisticated preclinical models and techniques may improve the prediction of clinical treatment efficacy.

Original languageEnglish
Article number102466
JournalCancer treatment reviews
Volume110
DOIs
Publication statusPublished - 1 Nov 2022
Externally publishedYes

Keywords

  • Colorectal cancer
  • Preclinical models
  • Translational gaps
  • Tyrosine kinase inhibitors

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Iyer, K. K., van Erp, N. P., Tauriello, D. V. F., Verheul, H. M. W., & Poel, D. (2022). Lost in translation: Revisiting the use of tyrosine kinase inhibitors in colorectal cancer. Cancer treatment reviews, 110, Article 102466. https://doi.org/10.1016/j.ctrv.2022.102466

Iyer, Kirti K. ; van Erp, Nielka P. ; Tauriello, Daniele V. F. et al. / Lost in translation : Revisiting the use of tyrosine kinase inhibitors in colorectal cancer. In: Cancer treatment reviews. 2022 ; Vol. 110.

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abstract = "Patients with advanced or metastatic colorectal cancer ((m)CRC) have limited effective treatment options resulting in high mortality rates. A better understanding of the molecular basis of this disease has led to growing interest in small molecule tyrosine kinase inhibitors (TKIs) for its treatment. However, of around 42 TKIs demonstrating preclinical anti-tumour activity, and despite numerous clinical trials, only 1 has been approved for clinical use in mCRC. Clearly, there is a huge gap in the translation of these targeted therapies to the clinic. This underlines the limitations of preclinical models to predict clinical drug efficacy and to fully characterize the mechanism of action. Moreover, several relevant topics remain poorly resolved. Do we know the actual intracellular concentrations that are required for anticancer efficacy, and what range of intra-tumoral drug concentrations is reached in clinical setting? Are the intended targeted kinases responsible for the anti-cancer activity or are other unexpected cellular targets involved? Do we have any idea of the effect of these drugs on the tumour microenvironment and does this help explain therapy success, failure or heterogeneity? In this review, we address these questions and discuss concepts that jointly complicate the clinical translation of TKIs for CRC. Finally, we will argue that an integrated approach with more sophisticated preclinical models and techniques may improve the prediction of clinical treatment efficacy.",

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author = "Iyer, {Kirti K.} and {van Erp}, {Nielka P.} and Tauriello, {Daniele V. F.} and Verheul, {Henk M. W.} and Dennis Poel",

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Iyer, KK, van Erp, NP, Tauriello, DVF, Verheul, HMW & Poel, D 2022, 'Lost in translation: Revisiting the use of tyrosine kinase inhibitors in colorectal cancer', Cancer treatment reviews, vol. 110, 102466. https://doi.org/10.1016/j.ctrv.2022.102466

Lost in translation: Revisiting the use of tyrosine kinase inhibitors in colorectal cancer. / Iyer, Kirti K.; van Erp, Nielka P.; Tauriello, Daniele V. F. et al.
In: Cancer treatment reviews, Vol. 110, 102466, 01.11.2022.

Research output: Contribution to journalReview articleAcademicpeer-review

TY - JOUR

T1 - Lost in translation

T2 - Revisiting the use of tyrosine kinase inhibitors in colorectal cancer

AU - Iyer, Kirti K.

AU - van Erp, Nielka P.

AU - Tauriello, Daniele V. F.

AU - Verheul, Henk M. W.

AU - Poel, Dennis

N1 - Funding Information:DVFT is funded by a Hypatia Fellowship from the Radboudumc.Publisher Copyright:© 2022 The Author(s)

PY - 2022/11/1

Y1 - 2022/11/1

N2 - Patients with advanced or metastatic colorectal cancer ((m)CRC) have limited effective treatment options resulting in high mortality rates. A better understanding of the molecular basis of this disease has led to growing interest in small molecule tyrosine kinase inhibitors (TKIs) for its treatment. However, of around 42 TKIs demonstrating preclinical anti-tumour activity, and despite numerous clinical trials, only 1 has been approved for clinical use in mCRC. Clearly, there is a huge gap in the translation of these targeted therapies to the clinic. This underlines the limitations of preclinical models to predict clinical drug efficacy and to fully characterize the mechanism of action. Moreover, several relevant topics remain poorly resolved. Do we know the actual intracellular concentrations that are required for anticancer efficacy, and what range of intra-tumoral drug concentrations is reached in clinical setting? Are the intended targeted kinases responsible for the anti-cancer activity or are other unexpected cellular targets involved? Do we have any idea of the effect of these drugs on the tumour microenvironment and does this help explain therapy success, failure or heterogeneity? In this review, we address these questions and discuss concepts that jointly complicate the clinical translation of TKIs for CRC. Finally, we will argue that an integrated approach with more sophisticated preclinical models and techniques may improve the prediction of clinical treatment efficacy.

AB - Patients with advanced or metastatic colorectal cancer ((m)CRC) have limited effective treatment options resulting in high mortality rates. A better understanding of the molecular basis of this disease has led to growing interest in small molecule tyrosine kinase inhibitors (TKIs) for its treatment. However, of around 42 TKIs demonstrating preclinical anti-tumour activity, and despite numerous clinical trials, only 1 has been approved for clinical use in mCRC. Clearly, there is a huge gap in the translation of these targeted therapies to the clinic. This underlines the limitations of preclinical models to predict clinical drug efficacy and to fully characterize the mechanism of action. Moreover, several relevant topics remain poorly resolved. Do we know the actual intracellular concentrations that are required for anticancer efficacy, and what range of intra-tumoral drug concentrations is reached in clinical setting? Are the intended targeted kinases responsible for the anti-cancer activity or are other unexpected cellular targets involved? Do we have any idea of the effect of these drugs on the tumour microenvironment and does this help explain therapy success, failure or heterogeneity? In this review, we address these questions and discuss concepts that jointly complicate the clinical translation of TKIs for CRC. Finally, we will argue that an integrated approach with more sophisticated preclinical models and techniques may improve the prediction of clinical treatment efficacy.

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KW - Preclinical models

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JO - Cancer treatment reviews

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Iyer KK, van Erp NP, Tauriello DVF, Verheul HMW, Poel D. Lost in translation: Revisiting the use of tyrosine kinase inhibitors in colorectal cancer. Cancer treatment reviews. 2022 Nov 1;110:102466. doi: 10.1016/j.ctrv.2022.102466

Lost in translation: Revisiting the use of tyrosine kinase inhibitors in colorectal cancer (2024)
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