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PIM kinase inhibition: co-targeted therapeutic approaches in prostate cancer.
Signal Transduction and Targeted Therapy ( IF 40.8 ) Pub Date : 2020-01-31 , DOI: 10.1038/s41392-020-0109-y Sabina Luszczak 1 , Christopher Kumar 1 , Vignesh Krishna Sathyadevan 1 , Benjamin S Simpson 1 , Kathy A Gately 2 , Hayley C Whitaker 1 , Susan Heavey 1
Signal Transduction and Targeted Therapy ( IF 40.8 ) Pub Date : 2020-01-31 , DOI: 10.1038/s41392-020-0109-y Sabina Luszczak 1 , Christopher Kumar 1 , Vignesh Krishna Sathyadevan 1 , Benjamin S Simpson 1 , Kathy A Gately 2 , Hayley C Whitaker 1 , Susan Heavey 1
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PIM kinases have been shown to play a role in prostate cancer development and progression, as well as in some of the hallmarks of cancer, especially proliferation and apoptosis. Their upregulation in prostate cancer has been correlated with decreased patient overall survival and therapy resistance. Initial efforts to inhibit PIM with monotherapies have been hampered by compensatory upregulation of other pathways and drug toxicity, and as such, it has been suggested that co-targeting PIM with other treatment approaches may permit lower doses and be a more viable option in the clinic. Here, we present the rationale and basis for co-targeting PIM with inhibitors of PI3K/mTOR/AKT, JAK/STAT, MYC, stemness, and RNA Polymerase I transcription, along with other therapies, including androgen deprivation, radiotherapy, chemotherapy, and immunotherapy. Such combined approaches could potentially be used as neoadjuvant therapies, limiting the development of resistance to treatments or sensitizing cells to other therapeutics. To determine which drugs should be combined with PIM inhibitors for each patient, it will be key to develop companion diagnostics that predict response to each co-targeted option, hopefully providing a personalized medicine pathway for subsets of prostate cancer patients in the future.
中文翻译：
PIM 激酶抑制：前列腺癌的联合靶向治疗方法。
PIM 激酶已被证明在前列腺癌的发生和进展以及癌症的一些特征中发挥作用，尤其是增殖和细胞凋亡。它们在前列腺癌中的上调与患者总体生存率和治疗耐药性的降低相关。最初用单一疗法抑制 PIM 的努力因其他途径的代偿性上调和药物毒性而受到阻碍，因此，有人建议将 PIM 与其他治疗方法共同靶向可能会降低剂量，并成为临床上更可行的选择。在此，我们介绍了使用 PI3K/mTOR/AKT、JAK/STAT、MYC、干性和 RNA 聚合酶 I 转录抑制剂共同靶向 PIM 的基本原理和基础，以及其他疗法，包括雄激素剥夺、放疗、化疗和免疫疗法。这种组合方法有可能用作新辅助疗法，限制治疗耐药性的发展或使细胞对其他疗法敏感。为了确定每位患者应将哪些药物与 PIM 抑制剂联合使用，开发伴随诊断来预测对每种联合靶向选项的反应将是关键，有望为未来的前列腺癌患者亚群提供个性化的医疗途径。
更新日期：2020-01-31
中文翻译：
PIM 激酶抑制：前列腺癌的联合靶向治疗方法。
PIM 激酶已被证明在前列腺癌的发生和进展以及癌症的一些特征中发挥作用，尤其是增殖和细胞凋亡。它们在前列腺癌中的上调与患者总体生存率和治疗耐药性的降低相关。最初用单一疗法抑制 PIM 的努力因其他途径的代偿性上调和药物毒性而受到阻碍，因此，有人建议将 PIM 与其他治疗方法共同靶向可能会降低剂量，并成为临床上更可行的选择。在此，我们介绍了使用 PI3K/mTOR/AKT、JAK/STAT、MYC、干性和 RNA 聚合酶 I 转录抑制剂共同靶向 PIM 的基本原理和基础，以及其他疗法，包括雄激素剥夺、放疗、化疗和免疫疗法。这种组合方法有可能用作新辅助疗法，限制治疗耐药性的发展或使细胞对其他疗法敏感。为了确定每位患者应将哪些药物与 PIM 抑制剂联合使用，开发伴随诊断来预测对每种联合靶向选项的反应将是关键，有望为未来的前列腺癌患者亚群提供个性化的医疗途径。
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