Resistance to conventional anti-tumor drugs is one of the significant challenges in oncology, responsible for treatment failure and patient death. Introduction of the targeted drugs (e.g., small molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies) in cancer therapy significantly improved overall survival (OS) and progression-free survival (PFS) rates for selected groups of cancer patients and delayed the progression of advanced forms of human malignancies. However, the development of secondary resistance to the targeted drugs remains an unbeatable obstacle to a successful outcome in the long run, thereby making prognosis unfavorable for cancer patients with advanced, recurrent, and metastatic forms of disease. The review focuses on several mechanisms that regulate cancer resistance to conventional chemotherapies. This includes the upregulation of main types of ABC transporters (e.g., ABCB1, ABCC1, and ABCG2), which provides the efflux of chemotherapeutic agents from cancer cells. Additionally, the activation of diverse DNA damage repair (DDR) pathways, epithelial-to-mesenchymal transition (EMT), and the population of cancer stem cells (CSCs) are also discussed in detail, thereby illustrating the diverse molecular mechanisms of cancer sensitivity to chemotherapies. Recently, several TKIs, including those that were initially developed to specifically target FGFR and VEGFR pathways, have also been reported to exhibit “off-target” effects by interacting with ABC transporters and inhibiting their function. This, in turn, illustrates their potency in retaining chemotherapeutic agents within cancer cells and possessing a chemosensitizing function. Of note, FGFR and VEGFR inhibitors may behave as inhibitors or substrates of ABC transporters, depending on the expression of specific pumps and affinity for them, concentrations, and types of co-administered agents, thereby disclosing the complexity of this scenario. Additionally, the aforementioned RTKI can interfere with the other molecular mechanisms regulating tumor sensitivity to conventional chemotherapies, including the regulation of diverse DDR pathways, EMT, and the population of CSCs. Thereby, the aforementioned “off-target” functions of FGFR and VEGFR inhibitors can open novel approaches towards anti-cancer therapies and strategies aimed at counteracting cancer multidrug resistance (MDR), which is important especially as second- or third-line treatments in patients who have progressed on modern chemotherapeutic regimens. Notably, the strategy of using TKIs to potentiate the clinical efficacy of chemotherapies can extend beyond inhibitors of FGFR and VEGFR signaling pathways, thereby providing a rationale for repurposing existing TKIs as an attractive therapeutic approach to overcome cancer chemoresistance.
对常规抗肿瘤药物的耐药性是肿瘤学领域的重大挑战之一，常导致治疗失败和患者死亡。靶向药物（如小分子酪氨酸激酶抑制剂和单克隆抗体）在癌症治疗中的应用，显著提高了特定癌症患者群体的总生存期和无进展生存期，并延缓了晚期恶性肿瘤的进展。然而，靶向药物继发性耐药的发展，长期来看仍是影响治疗成功难以逾越的障碍，使得晚期、复发性和转移性癌症患者的预后不佳。本综述重点探讨了调控癌症对常规化疗耐药的几种机制，包括主要ABC转运蛋白（如ABCB1、ABCC1和ABCG2）的上调，这些蛋白能将化疗药物泵出癌细胞。此外，还详细讨论了多种DNA损伤修复通路的激活、上皮-间质转化以及癌症干细胞群，从而阐明了癌症对化疗敏感性的多种分子机制。最近有报道称，包括最初为特异性靶向FGFR和VEGFR通路而开发的几种酪氨酸激酶抑制剂，通过与ABC转运蛋白相互作用并抑制其功能，也表现出“脱靶”效应。这反过来表明它们在将化疗药物保留在癌细胞中并发挥化疗增敏作用方面的潜力。值得注意的是，FGFR和VEGFR抑制剂可能作为ABC转运蛋白的抑制剂或底物，具体取决于特定泵的表达及其亲和力、浓度以及联合用药的类型，从而揭示了这一情况的复杂性。此外，上述受体酪氨酸激酶抑制剂还能干扰其他调控肿瘤对常规化疗敏感性的分子机制，包括调控多种DNA损伤修复通路、上皮-间质转化以及癌症干细胞群。因此，FGFR和VEGFR抑制剂的上述“脱靶”功能，可能为抗癌治疗和旨在对抗癌症多药耐药性的策略开辟新途径，这对于在现代化疗方案中病情进展的患者作为二线或三线治疗尤为重要。值得注意的是，利用酪氨酸激酶抑制剂增强化疗临床疗效的策略，可扩展至FGFR和VEGFR信号通路抑制剂之外，从而为重新利用现有酪氨酸激酶抑制剂作为克服癌症化疗耐药性的有吸引力的治疗方法提供了理论依据。
肿瘤(癌症)患者之家