化学耐药性是癌症治疗的主要障碍，常常导致疾病进展和不良结果。它是通过多种机制产生的，例如基因突变、药物外排泵、增强的 DNA 修复和肿瘤微环境的变化。这些过程使得癌细胞在化疗的情况下仍能存活，这凸显了需要新的策略来克服耐药性并提高治疗效果。克唑替尼是第一代多靶点激酶抑制剂，被 FDA 批准用于治疗 ALK 阳性或 ROS1 阳性非小细胞肺癌（NSCLC）、难治性炎症（ALK）阳性肌纤维母细胞瘤（IMT）以及复发/难治性 ALK 阳性间变性大细胞淋巴瘤 (ALCL)。克唑替尼以两种对映体形式存在：(R)-克唑替尼及其镜像，(S)-克唑替尼。据推测，R 异构体负责执行本文所述的各种过程。另一方面，S 异构体对 MTH1（一种对 DNA 修复机制很重要的酶）表现出强烈的抑制作用。研究表明，克唑替尼是一种有效的多激酶抑制剂，针对多种激酶，如 c-Met、native/T315I Bcr/Abl 和 JAK2。其作用机制涉及 ATP 结合的竞争性抑制和变构抑制，特别是 Bcr/Abl。克唑替尼与聚 ADP 核糖聚合酶抑制剂 (PARP) 联合使用时显示出协同作用，特别是在治疗含有 BRCA 基因突变的卵巢癌中。此外，克唑替尼还针对许多 p53 突变癌症的一个关键弱点。与野生型对应物不同，p53 突变体可促进癌细胞存活。克唑替尼可引起 p53 突变体降解，使这些癌细胞对 DNA 损伤物质敏感并引发细胞凋亡。有趣的是，其他报告表明克唑替尼具有针对革兰氏阳性菌的抗菌活性。此外，它还具有对抗耐药菌株的活性。综上所述，克唑替尼通过多种机制发挥抗肿瘤作用，包括抑制激酶和恢复药物敏感性。克唑替尼在联合治疗中的潜力得到了强调，特别是在 p53 突变体患病率较高的癌症中，例如三阴性乳腺癌 (TNBC) 和高级别浆液性卵巢癌 (HGSOC)。

Chemoresistance is a major obstacle in cancer treatment, often leading to disease progression and poor outcomes. It arises through various mechanisms such as genetic mutations, drug efflux pumps, enhanced DNA repair, and changes in the tumor microenvironment. These processes allow cancer cells to survive despite chemotherapy, underscoring the need for new strategies to overcome resistance and improve treatment efficacy. Crizotinib, a first-generation multi-target kinase inhibitor, is approved by the FDA for the treatment of ALK-positive or ROS1-positive non-small cell lung cancer (NSCLC), refractory inflammatory (ALK)-positive myofibroblastic tumors (IMTs) and relapsed/refractory ALK-positive anaplastic large cell lymphoma (ALCL). Crizotinib exists in two enantiomeric forms: (R)-crizotinib and its mirror image, (S)-crizotinib. It is assumed that the R-isomer is responsible for the carrying out various processes reviewed here The S-isomer, on the other hand, shows a strong inhibition of MTH1, an enzyme important for DNA repair mechanisms. Studies have shown that crizotinib is an effective multi-kinase inhibitor targeting various kinases such as c-Met, native/T315I Bcr/Abl, and JAK2. Its mechanism of action involves the competitive inhibition of ATP binding and allosteric inhibition, particularly at Bcr/Abl. Crizotinib showed synergistic effects when combined with the poly ADP ribose polymerase inhibitor (PARP), especially in ovarian cancer harboring BRCA gene mutations. In addition, crizotinib targets a critical vulnerability in many p53-mutated cancers. Unlike its wild-type counterpart, the p53 mutant promotes cancer cell survival. Crizotinib can cause the degradation of the p53 mutant, sensitizing these cancer cells to DNA-damaging substances and triggering apoptosis. Interestingly, other reports demonstrated that crizotinib exhibits anti-bacterial activity, targeting Gram-positive bacteria. Also, it is active against drug-resistant strains. In summary, crizotinib exerts anti-tumor effects through several mechanisms, including the inhibition of kinases and the restoration of drug sensitivity. The potential of crizotinib in combination therapies is emphasized, particularly in cancers with a high prevalence of the p53 mutant, such as triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSOC).