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在非小细胞肺癌中共同靶向PIM激酶和PI3K/mTOR

Co-Targeting PIM Kinase and PI3K/mTOR in NSCLC.

作者信息

Moore Gillian, Lightner Clara, Elbai Samira, Brady Lauren, Nicholson Siobhan, Ryan Ronan, O'Sullivan Katie E, O'Byrne Kenneth J, Blanco-Aparicio Carmen, Cuffe Sinead, O'Neill Michael, Heavey Susan, Finn Stephen P, Gately Kathy

机构信息

Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James's Hospital, Dublin, Ireland.

School of Pharmacy and Biomolecular Sciences, RCSI, Dublin, Ireland.

出版信息

Cancers (Basel). 2021 Apr 29;13(9):2139. doi: 10.3390/cancers13092139.

DOI:10.3390/cancers13092139
PMID:33946744
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8125027/
Abstract

PIM kinases are constitutively active proto-oncogenic serine/threonine kinases that play a role in cell cycle progression, metabolism, inflammation and drug resistance. PIM kinases interact with and stabilize p53, c-Myc and parallel signaling pathway PI3K/Akt. This study evaluated PIM kinase expression in NSCLC and in response to PI3K/mTOR inhibition. It investigated a novel preclinical PI3K/mTOR/PIM inhibitor (IBL-301) in vitro and in patient-derived NSCLC tumor tissues. Western blot analysis confirmed PIM1, PIM2 and PIM3 are expressed in NSCLC cell lines and PIM1 is a marker of poor prognosis in patients with NSCLC. IBL-301 decreased PIM1, c-Myc, pBAD and p4EBP1 (Thr37/46) and peIF4B (S406) protein levels in-vitro and MAP kinase, PI3K-Akt and JAK/STAT pathways in tumor tissue explants. IBL-301 significantly decreased secreted pro-inflammatory cytokine MCP-1. Altered mRNA expression, including activated PIM kinase and c-Myc, was identified in Apitolisib resistant cells (H1975GR) by an IL-6/STAT3 pathway array and validated by Western blot. H1975GR cells were more sensitive to IBL-301 than parent cells. A miRNA array identified a dysregulated miRNA signature of PI3K/mTOR drug resistance consisting of regulators of PIM kinase and c-Myc (miR17-5p, miR19b-3p, miR20a-5p, miR15b-5p, miR203a, miR-206). Our data provides a rationale for co-targeting PIM kinase and PI3K-mTOR to improve therapeutic response in NSCLC.

摘要

PIM激酶是组成型激活的原癌基因丝氨酸/苏氨酸激酶，在细胞周期进程、代谢、炎症和耐药性中发挥作用。PIM激酶与p53、c-Myc以及平行信号通路PI3K/Akt相互作用并使其稳定。本研究评估了PIM激酶在非小细胞肺癌（NSCLC）中的表达以及对PI3K/mTOR抑制的反应。它在体外和患者来源的NSCLC肿瘤组织中研究了一种新型的临床前PI3K/mTOR/PIM抑制剂（IBL-301）。蛋白质印迹分析证实PIM1、PIM2和PIM3在NSCLC细胞系中表达，且PIM1是NSCLC患者预后不良的标志物。IBL-301在体外降低了PIM1、c-Myc、pBAD和p4EBP1（Thr37/46）以及peIF4B（S406）的蛋白质水平，并降低了肿瘤组织外植体中的丝裂原活化蛋白激酶、PI3K-Akt和JAK/STAT通路。IBL-301显著降低了分泌的促炎细胞因子MCP-1。通过IL-6/STAT3通路阵列在阿培利司耐药细胞（H1975GR）中鉴定出包括激活的PIM激酶和c-Myc在内的mRNA表达改变，并通过蛋白质印迹进行了验证。H1975GR细胞比亲本细胞对IBL-301更敏感。一项miRNA阵列鉴定出由PIM激酶和c-Myc的调节因子（miR17-5p、miR19b-3p、miR20a-5p、miR15b-5p、miR203a、miR-206）组成的PI3K/mTOR耐药性失调的miRNA特征。我们的数据为联合靶向PIM激酶和PI3K-mTOR以改善NSCLC的治疗反应提供了理论依据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b09b/8125027/eba38bb12be2/cancers-13-02139-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b09b/8125027/b1aa26d1d983/cancers-13-02139-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b09b/8125027/91fb1f4af14c/cancers-13-02139-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b09b/8125027/022f8bd9f11f/cancers-13-02139-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b09b/8125027/e8d63ef4ff39/cancers-13-02139-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b09b/8125027/1c16ff720e49/cancers-13-02139-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b09b/8125027/54484e93fe2b/cancers-13-02139-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b09b/8125027/362b6ed75768/cancers-13-02139-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b09b/8125027/eba38bb12be2/cancers-13-02139-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b09b/8125027/b1aa26d1d983/cancers-13-02139-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b09b/8125027/91fb1f4af14c/cancers-13-02139-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b09b/8125027/022f8bd9f11f/cancers-13-02139-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b09b/8125027/e8d63ef4ff39/cancers-13-02139-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b09b/8125027/1c16ff720e49/cancers-13-02139-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b09b/8125027/54484e93fe2b/cancers-13-02139-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b09b/8125027/362b6ed75768/cancers-13-02139-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b09b/8125027/eba38bb12be2/cancers-13-02139-g008.jpg

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