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).
化疗耐药是癌症治疗中的主要障碍，常导致疾病进展和不良预后。其产生机制多样，包括基因突变、药物外排泵作用增强、DNA修复能力提升以及肿瘤微环境改变等。这些过程使得癌细胞能够在化疗中存活，凸显了开发新策略以克服耐药性、提高治疗效果的迫切需求。克唑替尼作为第一代多靶点激酶抑制剂，已获美国食品药品监督管理局批准用于治疗ALK阳性或ROS1阳性非小细胞肺癌、难治性炎症性（ALK阳性）肌纤维母细胞瘤以及复发/难治性ALK阳性间变性大细胞淋巴瘤。克唑替尼存在两种对映异构体形式：（R）-克唑替尼及其镜像异构体（S）-克唑替尼。一般认为R-异构体负责执行本文综述的多种作用机制，而S-异构体则对DNA修复关键酶MTH1表现出强效抑制作用。研究表明，克唑替尼是能靶向c-Met、野生型/T315I突变型Bcr/Abl及JAK2等多种激酶的高效多激酶抑制剂。其作用机制涉及ATP结合竞争性抑制和变构抑制，尤其在Bcr/Abl靶点表现显著。当与聚ADP核糖聚合酶抑制剂联用时，克唑替尼在携带BRCA基因突变的卵巢癌中展现出协同增效作用。此外，克唑替尼能靶向许多p53突变癌症的关键脆弱点。与野生型p53不同，突变型p53会促进癌细胞存活。克唑替尼可诱导突变型p53降解，使这些癌细胞对DNA损伤物质敏感并触发细胞凋亡。值得注意的是，另有研究证实克唑替尼对革兰氏阳性菌具有抗菌活性，且对耐药菌株同样有效。综上所述，克唑替尼通过抑制激酶活性、恢复药物敏感性等多种机制发挥抗肿瘤作用。其在联合疗法中的应用潜力值得重点关注，特别是在p53突变高发的癌症类型中，如三阴性乳腺癌和高级别浆液性卵巢癌。
Overcoming Chemoresistance in Cancer: The Promise of Crizotinib
肿瘤(癌症)患者之家