Many cancer patients frequently fail to respond to anti-cancer treatment due to therapy resistance which is the major obstacle towards curative cancer treatment. Therefore, identification of the molecular mechanisms underlying resistance is of paramount clinical and economic importance. The advent of targeted therapies based on a molecular understanding of cancer could serve as a model for strategies to overcome drug resistance. Accordingly, the identification and validation of proteins critically involved in resistance mechanisms represent a path towards innovative therapeutic strategies to improve the clinical outcome of cancer patients. In this review, we discuss emerging targets, small molecule therapeutics and drug delivery strategies to overcome therapy resistance. We focus on rational treatment strategies based on transcription factors, pseudokinases, nuclear export receptors and immunogenic cell death strategy. Historically, unliganded transcription factors and pseudokinases were considered undruggable while blocking the nuclear export e.g., through inhibition of the nuclear export receptor CRM1 was predicted as highly toxic. Recent success inhibiting Gli-1, HIF-1α, HIF-2α and reactivating the tumor suppressor transcription factors p53 and FOXO illustrates the feasibility and power of this targeting approach. Similarly, progress has been made in modulating the activity of pseudokinase proteins implicated in therapy resistance including members of the Tribbles protein family. On the other hand, the recent clinical approval of Selinexor, a specific inhibitor of CRM-1, a protein that mediates the transport of cargos with leucine-rich nuclear export signals and known to be a driver of drug resistance, represents the proof-of-concept for inhibiting the nuclear export as a feasible strategy to overcome therapy resistance.

The ever-growing capacity to target resistance mechanisms with judiciously selected small molecules, some of which are being formulated within smart nanoparticles, will pave the way towards the improvement of the clinical outcome and realize the full potential of targeted therapies and immunotherapies.

由于治疗抗性，许多癌症患者经常无法对抗癌治疗作出反应，这是治愈性癌症治疗的主要障碍。因此，识别耐药性的分子机制具有至关重要的临床和经济意义。基于对癌症的分子理解的靶向疗法的出现可以作为克服耐药性策略的模型。因此，与耐药机制密切相关的蛋白质的鉴定和验证代表了通往创新治疗策略以改善癌症患者临床结果的途径。在这篇综述中，我们讨论了克服治疗耐药性的新兴靶点、小分子疗法和药物递送策略。我们专注于基于转录因子的合理治疗策略，假激酶，核输出受体和免疫原性细胞死亡策略。从历史上看，未配体转录因子和假激酶被认为是不可成药的，同时会阻止核输出例如，通过抑制核输出受体 CRM1 被预测为剧毒。最近成功抑制 Gli-1、HIF-1α、HIF-2α 并重新激活肿瘤抑制转录因子 p53 和 FOXO 说明了这种靶向方法的可行性和威力。同样，在调节与治疗抗性有关的假激酶蛋白（包括 Tribbles 蛋白家族成员）的活性方面也取得了进展。另一方面，最近临床批准的 Selinexor 是 CRM-1 的特异性抑制剂，CRM-1 是一种介导具有富含亮氨酸的核输出信号的货物运输的蛋白质，已知是耐药性的驱动因素，代表了- 将抑制核输出作为克服治疗抗性的可行策略的概念。

使用明智选择的小分子（其中一些正在智能纳米粒子中配制）靶向耐药机制的能力不断增长，将为改善临床结果铺平道路，并实现靶向治疗和免疫疗法的全部潜力。