PI3K信号通路过度激活对非霍奇金淋巴瘤患者预后的影响及其靶向药物疗效

国际肿瘤学杂志››2021,Vol. 48››Issue (2): 121-124.doi:10.3760/cma.j.cn371439-20200615-00024

PI3K信号通路过度激活对非霍奇金淋巴瘤患者预后的影响及其靶向药物疗效

乔薇¹, 宋腾², 陈馨蕊¹, 王华庆²()

¹天津医科大学研究生院 300070
²天津市人民医院肿瘤诊治中心天津市中西医结合肿瘤研究所 300121

收稿日期:2020-06-15修回日期:2020-07-14出版日期:2021-02-08发布日期:2021-03-11
通讯作者:王华庆 E-mail:huaqingw@163.com

Effect of excessive activation of PI3K signaling pathway on the prognosis of patients with non-Hodgkin lymphoma and the efficacy of targeted drugs

Qiao Wei¹, Song Teng², Chen Xinrui¹, Wang Huaqing²()

¹Graduate School of Tianjin Medical University, Tianjin 300070, China
²Department of Medical Oncology, Tianjin Union Medical Center; Tianjin Cancer Research Institute of Traditional Chinese and Westen Medicine, Tianjin 300121, China

Received:2020-06-15Revised:2020-07-14Online:2021-02-08Published:2021-03-11
Contact:Wang Huaqing E-mail:huaqingw@163.com

摘要/Abstract

摘要：

磷脂酰肌醇3-激酶(PI3K)/蛋白激酶B(Akt)/雷帕霉素靶蛋白(mTOR)信号通路过度激活与恶性肿瘤的发生发展及临床预后密切相关,以该信号通路为靶点的治疗药物可以有效抑制肿瘤的进展。目前美国食品和药物监督管理局批准了3种药物(CAL-101、BAY80-6946、IPI-145)用于治疗复发和难治性惰性非霍奇金淋巴瘤,临床上显示出显著的疗效和可控的安全性。

关键词:淋巴瘤,磷酸酰肌醇类,分子靶向治疗

Abstract:

The over-activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mechanistic target of rapamcyin (mTOR) pathway is closely related to the occurrence, development and clinical prognosis of malignant tumors. Taking this signal pathway as a target can effectively inhibit tumor progression. At present, the Food and Drug Administration of the United States has approved three drugs (CAL-101, BAY80-6946, IPI-145) for the treatment of recurrent and refractory indolent non-Hodgkin lymphoma, which demonstrates significant efficacy and a manageable safety profile.

Key words:Lymphoma,Phosphatidylinositols,Molecular targeted therapy

乔薇, 宋腾, 陈馨蕊, 王华庆. PI3K信号通路过度激活对非霍奇金淋巴瘤患者预后的影响及其靶向药物疗效[J]. 国际肿瘤学杂志, 2021, 48(2): 121-124.

Qiao Wei, Song Teng, Chen Xinrui, Wang Huaqing. Effect of excessive activation of PI3K signaling pathway on the prognosis of patients with non-Hodgkin lymphoma and the efficacy of targeted drugs[J]. Journal of International Oncology, 2021, 48(2): 121-124.

参考文献27

[1]	Jain T, Sauter CS, Shah GL, et al. Safety and feasibility of chimeric antigen receptor T cell therapy after allogeneic hematopoietic cell transplantation in relapsed/refractory B cell non-Hodgkin lymphoma[J]. Leukemia, 2019,33(10):2540-2544. DOI: 10.1038/s41375-019-0476-y. doi:10.1038/s41375-019-0476-ypmid:31114023
[2]	Yuan T, Yang Y, Chen J, et al. Regulation of PI3K signaling in T-cell acute lymphoblastic leukemia: a novel PTEN/Ikaros/miR-26b mechanism reveals a critical targetable role for PIK3CD[J]. Leukemia, 2017,31(11):2355-2364. DOI: 10.1038/leu.2017.80. doi:10.1038/leu.2017.80pmid:28280276
[3]	Yang J, Nie J, Ma X, et al. Targeting PI3K in cancer: mechanisms and advances in clinical trials[J]. Mol Cancer, 2019,18(1):26. DOI: 10.1186/s12943-019-0954-x. doi:10.1186/s12943-019-0954-xpmid:30782187
[4]	Sapon-Cousineau V, Sapon-Cousineau S, Assouline S. PI3K inhibitors and their role as novel agents for targeted therapy in lymphoma[J]. Curr Treat Options Oncol, 2020,21(6):51. DOI: 10.1007/s11864-020-00746-8. doi:10.1007/s11864-020-00746-8pmid:32356174
[5]	Manning BD, Toker A. AKT/PKB signaling: navigating the network[J]. Cell, 2017,169(3):381-405. DOI: 10.1016/j.cell.2017.04.001. doi:10.1016/j.cell.2017.04.001pmid:28431241
[6]	Luongo F, Colonna F, Calapà F, et al. PTEN tumor-suppressor: the dam of stemness in cancer[J]. Cancers (Basel), 2019,11(8):1076. DOI: 10.3390/cancers11081076. doi:10.3390/cancers11081076
[7]	Papa A, Wan L, Bonora M, et al. Cancer-associated PTEN mutants act in a dominant-negative manner to suppress PTEN protein function[J]. Cell, 2014,157(3):595-610. DOI: 10.1016/j.cell.2014.03.027. doi:10.1016/j.cell.2014.03.027
[8]	Li C, Xu Y, Xin P, et al. Role and mechanism of PTEN in Burkitt's lymphoma[J]. Oncol Rep, 2020,43(2):481-490. DOI: 10.3892/or.2020.7457. doi:10.3892/or.2020.7457pmid:31922234
[9]	Wang X, Cao X, Sun R, et al. Clinical significance of PTEN deletion, mutation, and loss of PTEN expression in de novo diffuse large B-cell lymphoma[J]. Neoplasia, 2018,20(6):574-593. DOI: 10.1016/j.neo.2018.03.002. doi:10.1016/j.neo.2018.03.002pmid:29734016
[10]	Okkenhaug K, Vanhaesebroeck B. PI3K in lymphocyte development, differentiation and activation[J]. Nat Rev Immunol, 2003,3(4):317-330. DOI: 10.1038/nri1056. doi:10.1038/nri1056pmid:12669022
[11]	Cui W, Cai Y, Wang W, et al. Frequent copy number variations of PI3K/AKT pathway and aberrant protein expressions of PI3K subunits are associated with inferior survival in diffuse large B cell lymphoma[J]. J Transl Med, 2014,12:10. DOI: 10.1186/1479-5876-12-10. doi:10.1186/1479-5876-12-10pmid:24418330
[12]	满杰, 陈莲, 翟晓文, 等. p-AKT/p-mTOR蛋白在儿童Burkitt淋巴瘤中的表达及其与预后的关系[J]. 中华病理学杂志, 2020,49(2):156-161. DOI: 10.3760/cma.j.issn.0529-5807.2020.02.010.
[13]	Hong JY, Hong ME, Choi MK, et al. The impact of activated p-AKT expression on clinical outcomes in diffuse large B-cell lymphoma: a clinicopathological study of 262 cases[J]. Ann Oncol, 2014,25(1):182-188. DOI: 10.1093/annonc/mdt530. doi:10.1093/annonc/mdt530pmid:24356628
[14]	Markham A. Idelalisib: first global approval[J]. Drugs, 2014,74(14):1701-1707. DOI: 10.1007/s40265-014-0285-6. doi:10.1007/s40265-014-0285-6
[15]	Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma[J]. N Engl J Med, 2014,370(11):1008-1018. DOI: 10.1056/NEJMoa1314583. doi:10.1056/NEJMoa1314583pmid:24450858
[16]	Eyre TA, Osborne WL, Gallop-Evans E, et al. Results of a multicentre UK-wide compassionate use programme evaluating the efficacy of idelalisib monotherapy in relapsed, refractory follicular lymphoma[J]. Br J Haematol, 2018,181(4):555-559. DOI: 10.1111/bjh.14665. doi:10.1111/bjh.14665pmid:28342183
[17]	O'Brien SM, Lamanna N, Kipps TJ, et al. A phase 2 study of idelalisib plus rituximab in treatment-naïve older patients with chronic lymphocytic leukemia[J]. Blood, 2015,126(25):2686-2694. DOI: 10.1182/blood-2015-03-630947. doi:10.1182/blood-2015-03-630947pmid:26472751
[18]	Jones JA, Robak T, Brown JR, et al. Efficacy and safety of idelalisib in combination with ofatumumab for previously treated chronic lymphocytic leukaemia: an open-label, randomised phase 3 trial[J]. Lancet Haematol, 2017,4(3):e114-e126. DOI: 10.1016/s2352-3026(17)30019-4. doi:10.1016/S2352-3026(17)30019-4pmid:28257752
[19]	Gopal AK, Fanale MA, Moskowitz CH, et al. Phase Ⅱ study of idelalisib, a selective inhibitor of PI3Kδ, for relapsed/refractory classical Hodgkin lymphoma[J]. Ann Oncol, 2017,28(5):1057-1063. DOI: 10.1093/annonc/mdx028. doi:10.1093/annonc/mdx028pmid:28327905
[20]	Dreyling M, Morschhauser F, Bouabdallah K, et al. Phase Ⅱ study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma[J]. Ann Oncol, 2017,28(9):2169-2178. DOI: 10.1093/annonc/mdx289. doi:10.1093/annonc/mdx289pmid:28633365
[21]	Dreyling M, Santoro A, Mollica L, et al. Phosphatidylinositol 3-kinase inhibition by copanlisib in relapsed or refractory indolent lymphoma[J]. J Clin Oncol, 2017,35(35):3898-3905. DOI: 10.1200/jco.2017.75.4648. doi:10.1200/JCO.2017.75.4648pmid:28976790
[22]	Markham A. Copanlisib: first global approval[J]. Drugs, 2017,77(18):2057-2062. DOI: 10.1007/s40265-017-0838-6. doi:10.1007/s40265-017-0838-6pmid:29127587
[23]	Dong S, Guinn D, Dubovsky JA, et al. IPI-145 antagonizes intrinsic and extrinsic survival signals in chronic lymphocytic leukemia cells[J]. Blood, 2014,124(24):3583-3586. DOI: 10.1182/blood-2014-07-587279. doi:10.1182/blood-2014-07-587279
[24]	Flinn IW, Miller CB, Ardeshna KM, et al. DYNAMO: a phase Ⅱ study of duvelisib (IPI-145) in patients with refractory indolent non-Hodgkin lymphoma[J]. J Clin Oncol, 2019,37(11):912-922. DOI: 10.1200/jco.18.00915. doi:10.1200/JCO.18.00915pmid:30742566
[25]	Flinn IW, Hillmen P, Montillo M, et al. The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL[J]. Blood, 2018,132(23):2446-2455. DOI: 10.1182/blood-2018-05-850461. doi:10.1182/blood-2018-05-850461pmid:30287523
[26]	Horwitz SM, Koch R, Porcu P, et al. Activity of the PI3K-δ, γ inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma[J]. Blood, 2018,131(8):888-898. DOI: 10.1182/blood-2017-08-802470. doi:10.1182/blood-2017-08-802470pmid:29233821
[27]	Wang HQ, Jiang WQ, Li S, et al. Safety and efficacy of TQ-B3525, a novel and selective oral PI3Kα/δ inhibitor, in Chinese patients with advanced malignancies: a phase Ⅰ dose-escalation and expansion trial [C/OL]//AACR Annual Meeting 2020: Session VCTPL04-Immunotherapy clinical trials 2. America, 2020[2020-06-15]. https://asco.confex.com/asco/2020/sci/papers/viewonly.cgi?password=862463&username=309305.