Alternative splicing is a tightly regulated process whereby non-coding sequences of pre-mRNA are removed and protein-coding segments are assembled in diverse combinations, ultimately giving rise to proteins with distinct or even opposing functions. In the past decade, whole genome/transcriptome sequencing studies revealed the high complexity of splicing regulation, which occurs co-transcriptionally and is influenced by chromatin status and mRNA modifications. Consequently, splicing profiles of both healthy and malignant cells display high diversity and alternative splicing was shown to be widely deregulated in multiple cancer types. In particular, mutations in pre-mRNA regulatory sequences, splicing regulators and chromatin modifiers, as well as differential expression of splicing factors are important contributors to cancer pathogenesis. It has become clear that these aberrations contribute to many facets of cancer, including oncogenic transformation, cancer progression, response to anticancer drug treatment as well as resistance to therapy. In this respect, alternative splicing was shown to perturb the expression a broad spectrum of relevant genes involved in drug uptake/metabolism (i.e. SLC29A1, dCK, FPGS, and TP), activation of nuclear receptor pathways (i.e. GR, AR), regulation of apoptosis (i.e. MCL1, BCL-X, and FAS) and modulation of response to immunotherapy (CD19). Furthermore, aberrant splicing constitutes an important source of novel cancer biomarkers and the spliceosome machinery represents an attractive target for a novel and rapidly expanding class of therapeutic agents. Small molecule inhibitors targeting SF3B1 or splice factor kinases were highly cytotoxic against a wide range of cancer models, including drug-resistant cells. Importantly, these effects are enhanced in specific cancer subsets, such as splicing factor-mutated and c-MYC-driven tumors. Furthermore, pre-clinical studies report synergistic effects of spliceosome modulators in combination with conventional antitumor agents. These strategies based on the use of low dose splicing modulators could shift the therapeutic window towards decreased toxicity in healthy tissues. Here we provide an extensive overview of the latest findings in the field of regulation of splicing in cancer, including molecular mechanisms by which cancer cells harness alternative splicing to drive oncogenesis and evade anticancer drug treatment as well as splicing-based vulnerabilities that can provide novel treatment opportunities. Furthermore, we discuss current challenges arising from genome-wide detection and prediction methods of aberrant splicing, as well as unravelling functional relevance of the plethora of cancer-related splicing alterations.

选择性剪接是一个严格调控的过程，通过这个过程，pre-mRNA 的非编码序列被去除，蛋白质编码片段以不同的组合组装，最终产生具有不同甚至相反功能的蛋白质。在过去的十年中，全基因组/转录组测序研究揭示了剪接调控的高度复杂性，该调控以共转录方式发生并受染色质状态和 mRNA 修饰的影响。因此，健康和恶性细胞的剪接图谱显示出高度的多样性，并且选择性剪接在多种癌症类型中被广泛解除管制。特别是，前 mRNA 调控序列、剪接调节因子和染色质修饰因子的突变以及剪接因子的差异表达是癌症发病机制的重要因素。很明显，这些畸变对癌症的许多方面都有影响，包括致癌转化、癌症进展、对抗癌药物治疗的反应以及对治疗的抵抗。在这方面，选择性剪接被证明会扰乱涉及药物摄取/代谢（即 SLC29A1、dCK、FPGS 和 TP）、核受体通路激活（即 GR、AR）、调节细胞凋亡（即 MCL1、BCL-X 和 FAS）和免疫治疗反应的调节（CD19）。此外，异常剪接构成了新型癌症生物标志物的重要来源，剪接体机制代表了一种新型且快速扩展的治疗剂类别的有吸引力的目标。针对 SF3B1 或剪接因子激酶的小分子抑制剂对多种癌症模型（包括耐药细胞）具有高度细胞毒性。重要的是，这些影响在特定的癌症亚群中得到增强，例如剪接因子突变和 c-MYC 驱动的肿瘤。此外，临床前研究报告了剪接体调节剂与常规抗肿瘤剂组合的协同作用。这些基于使用低剂量剪接调节剂的策略可以将治疗窗口转向降低健康组织的毒性。在这里，我们广泛概述了癌症剪接调控领域的最新发现，包括癌细胞利用选择性剪接来驱动肿瘤发生和逃避抗癌药物治疗的分子机制，以及可以提供新治疗机会的基于剪接的脆弱性。此外，我们讨论了当前由异常剪接的全基因组检测和预测方法所带来的挑战，以及解开大量癌症相关剪接改变的功能相关性。