PIM kinases are a class of serine/threonine kinases that play a role in several of the hallmarks of cancer including cell cycle progression, metabolism, inflammation and immune evasion. Their constitutively active nature and unique catalytic structure has led them to be an attractive anticancer target through the use of small molecule inhibitors. This review highlights the enhanced activity of PIM kinases in cancer that can be driven by hypoxia in the tumour microenvironment and the important role that aberrant PIM kinase activity plays in resistance mechanisms to chemotherapy, radiotherapy, anti-angiogenic therapies and targeted therapies. We highlight an interaction of PIM kinases with numerous major oncogenic players, including but not limited to, stabilisation of p53, synergism with c-Myc, and notable parallel signalling with PI3K/Akt. We provide a comprehensive overview of PIM kinase's role as an escape mechanism to targeted therapies including PI3K/mTOR inhibitors, MET inhibitors, anti-HER2/EGFR treatments and the immunosuppressant rapamycin, providing a rationale for co-targeting treatment strategies for a more durable patient response. The current status of PIM kinase inhibitors and their use as a combination therapy with other targeted agents, in addition to the development of novel multi-molecularly targeted single therapeutic agents containing a PIM kinase targeting moiety are discussed.

中文翻译：

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针对PIM激酶以克服癌症中的耐药性和免疫逃逸机制的当前观点。

PIM激酶是一类丝氨酸/苏氨酸激酶，在多种癌症特征中起作用，包括细胞周期进程，代谢，炎症和免疫逃逸。它们的组成活性性质和独特的催化结构使它们通过使用小分子抑制剂成为有吸引力的抗癌靶标。这篇综述强调了肿瘤微环境中的缺氧可能会导致PIM激酶在癌症中的活性增强，以及异常的PIM激酶活性在对化学疗法，放射疗法，抗血管生成疗法和靶向疗法的耐药机制中所起的重要作用。我们着重介绍了PIM激酶与众多主要致癌因子的相互作用，包括但不限于p53的稳定化，与c-Myc的协同作用以及与PI3K / Akt的显着平行信号传导。我们提供了有关PIM激酶作为靶向治疗的逃逸机制的作用的全面概述，包括PI3K / mTOR抑制剂，MET抑制剂，抗HER2 / EGFR治疗和雷帕霉素免疫抑制剂，为更持久的患者共同靶向治疗策略提供了理论依据回复。除了开发含有PIM激酶靶向部分的新型多分子靶向单一治疗剂外，还讨论了PIM激酶抑制剂的现状及其与其他靶向药物联合治疗的用途。为共同制定治疗策略提供了依据，以实现更持久的患者反应。除了开发含有PIM激酶靶向部分的新型多分子靶向单一治疗剂外，还讨论了PIM激酶抑制剂的现状及其与其他靶向药物联合治疗的用途。为共同制定治疗策略提供了依据，以实现更持久的患者反应。除了开发含有PIM激酶靶向部分的新型多分子靶向单一治疗剂外，还讨论了PIM激酶抑制剂的现状及其与其他靶向药物联合治疗的用途。