De Angelis Maria Laura, Francescangeli Federica, La Torre Filippo, Zeuner Ann
Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
Department of Surgical Sciences Policlinico Umberto I, Sapienza University of Rome, Rome, Italy.
Front Oncol. 2019 Jul 10;9:626. doi: 10.3389/fonc.2019.00626. eCollection 2019.
Cancer treatment with either standard chemotherapy or targeted agents often results in the emergence of drug-refractory cell populations, ultimately leading to therapy failure. The biological features of drug resistant cells are largely overlapping with those of cancer stem cells and include heterogeneity, plasticity, self-renewal ability, and tumor-initiating capacity. Moreover, drug resistance is usually characterized by a suppression of proliferation that can manifest as quiescence, dormancy, senescence, or proliferative slowdown. Alterations in key cellular pathways such as autophagy, unfolded protein response or redox signaling, as well as metabolic adaptations also contribute to the establishment of drug resistance, thus representing attractive therapeutic targets. Moreover, a complex interplay of drug resistant cells with the micro/macroenvironment and with the immune system plays a key role in dictating and maintaining the resistant phenotype. Recent studies have challenged traditional views of cancer drug resistance providing innovative perspectives, establishing new connections between drug resistant cells and their environment and indicating unexpected therapeutic strategies. In this review we discuss recent advancements in understanding the mechanisms underlying drug resistance and we report novel targeting agents able to overcome the drug resistant status, with particular focus on strategies directed against dormant cells. Research on drug resistant cancer cells will take us one step forward toward the development of novel treatment approaches and the improvement of relapse-free survival in solid and hematological cancer patients.
采用标准化疗或靶向药物进行癌症治疗往往会导致产生耐药细胞群体，最终导致治疗失败。耐药细胞的生物学特性在很大程度上与癌症干细胞的特性重叠，包括异质性、可塑性、自我更新能力和肿瘤起始能力。此外，耐药性通常表现为增殖受到抑制，可表现为静止、休眠、衰老或增殖减缓。关键细胞途径如自噬、未折叠蛋白反应或氧化还原信号的改变，以及代谢适应也有助于耐药性的形成，因此是有吸引力的治疗靶点。此外，耐药细胞与微/宏观环境以及免疫系统之间的复杂相互作用在决定和维持耐药表型方面起着关键作用。最近的研究对癌症耐药性的传统观点提出了挑战，提供了创新的观点，在耐药细胞与其环境之间建立了新的联系，并指出了意想不到的治疗策略。在这篇综述中，我们讨论了在理解耐药性潜在机制方面的最新进展，并报告了能够克服耐药状态的新型靶向药物，特别关注针对休眠细胞的策略。对耐药癌细胞的研究将使我们朝着开发新型治疗方法和提高实体癌和血液癌患者无复发生存率的方向迈进一步。
