Department of Medical Oncology, Radboud Institute for Health and Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands; Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.
Department of Pharmacy, Radboud Institute for Health and Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.
Cancer Treat Rev. 2022 Nov;110:102466. doi: 10.1016/j.ctrv.2022.102466. Epub 2022 Sep 21.
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.
患有晚期或转移性结直肠癌（mCRC）的患者有效的治疗选择有限，导致死亡率很高。对这种疾病的分子基础有了更好的理解，促使人们对小分子酪氨酸激酶抑制剂（TKI）治疗这种疾病产生了浓厚的兴趣。然而，在具有临床前抗肿瘤活性的约 42 种 TKI 中，尽管进行了大量临床试验，只有 1 种被批准用于 mCRC 的临床应用。显然，这些靶向治疗在向临床转化方面存在巨大差距。这突显出临床前模型在预测临床药物疗效和充分描述作用机制方面的局限性。此外，几个相关的主题仍然没有得到很好的解决。我们是否知道抗癌疗效所需的实际细胞内浓度，以及在临床环境中达到了多大的肿瘤内药物浓度？是预期的靶向激酶负责抗癌活性，还是涉及其他意想不到的细胞靶标？我们是否了解这些药物对肿瘤微环境的影响，这是否有助于解释治疗的成功、失败或异质性？在这篇综述中，我们将讨论这些问题，并讨论共同使 TKI 向 CRC 的临床转化复杂化的概念。最后，我们将认为，采用更复杂的临床前模型和技术的综合方法可能会提高对临床治疗疗效的预测。
