Suppression of Chromosome Instability Limits Acquired Drug Resistance.
Suppression of Chromosome Instability Limits Acquired Drug Resistance.
复制标题
DOI：
10.1158/1535-7163.mct-22-0263
复制
发表时间：
2022-10-07
影响因子：
5.7
通讯作者：
中科院分区：
文献类型：
--
作者：
数值染色体不稳定性，或nCIN，定义为整个染色体获得和丢失的高频率，在许多实体瘤中普遍存在。已显示nCIN促进肿瘤内异质性，并与肿瘤侵袭性、耐药性和肿瘤复发相对应。虽然增加的nCIN已被证明可促进导致耐药性的基因组变化的获得，但尚未充分探索以治疗方式调节nCIN的潜力。在此，我们评估nCIN在非小细胞肺癌获得耐药中的作用。我们发现，在非小细胞肺癌细胞中产生的整个染色体分离错误对微管动力学的操纵敏感，染色体凝聚力的增强强烈抑制了nCIN并降低了肿瘤内的异质性。我们证明抑制nCIN对体外非小细胞肺癌细胞增殖没有影响，也不影响小鼠异种移植模型中的肿瘤起始。然而，nCIN的抑制改变了驱动获得性耐药性的时间和分子机制。这些发现表明抑制nCIN的机制可以作为有效的联合治疗，以限制肿瘤演变和维持药物反应。
Numerical chromosome instability, or nCIN, defined as the high frequency of whole chromosome gains and losses, is prevalent in many solid tumors. nCIN has been shown to promote intra-tumor heterogeneity and corresponds with tumor aggressiveness, drug resistance and tumor relapse. While increased nCIN has been shown to promote the acquisition of genomic changes responsible for drug resistance, the potential to modulate nCIN in a therapeutic manner has not been well explored. Here we assess the role of nCIN in the acquisition of drug resistance in non small cell lung cancer. We show that generation of whole chromosome segregation errors in non small cell lung cancer cells is sensitive to manipulation of microtubule dynamics and that enhancement of chromosome cohesion strongly suppresses nCIN and reduces intra-tumor heterogeneity. We demonstrate that suppression of nCIN has no impact on non small cell lung cancer cell proliferation in vitro nor in tumor initiation in mouse xenograft models. However, suppression of nCIN alters the timing and molecular mechanisms that drive acquired drug resistance. These findings suggest mechanisms to suppress nCIN may serve as effective co-therapies to limit tumor evolution and sustain drug response.