KRAS基因突变的非小细胞肺癌靶向治疗进展
张煜坤 戈伟▲
武汉大学人民医院肿瘤Ⅱ科,湖北武汉 430060
Progress in targeted therapy of KRAS mutations in non-small cell lung cancer
ZHANG Yukun GE Wei▲
The Two Department of Oncology, Renmin Hospital of Wuhan University, Hubei Province, Wuhan 430060, China
摘要 肺癌是最致命的恶性肿瘤之一,高居全球肿瘤相关死亡的首位。随着多学科综合治疗的发展,肺癌患者的死亡率仍居高不下。KRAS基因突变是非小细胞肺癌最常见的突变类型。目前对KRAS基因突变的靶向治疗主要通过直接抑制KRAS基因、改变KRAS膜定位、抑制KRAS下游效应分子及抑制KRAS突变协同致死基因等方面进行研究。本文对KRAS基因突变的非小细胞肺癌靶向治疗的现况和进展进行综述。
关键词 :
非小细胞肺癌 ,
KRAS基因突变 ,
抑制KRAS下游效应分子 ,
靶向治疗
Abstract :Lung cancer is one of the most deadly malignancies, ranking the first in global cancer-related death. With the development of multidisciplinary comprehensive treatment, the mortality rate of patients with lung cancer is still high. KRAS gene mutations are the most common type of mutations in non-small cell lung. At present, the targeted therapy of KRAS gene mutation mainly through the direct inhibition of KRAS gene, change the KRAS membrane localization, inhibition of KRAS downstream effector molecules, inhibition of KRAS mutant synergistic lethal genes and other aspects of research. In this review, the status and progress of KRAS mutations in non-small cell lung cancer targeted therapy are briefly reviewed.
Key words :
Non-small cell lung cancer
KRAS gene mutation
Inhibition of KRAS downstream effector molecule
Targeting therapy
基金资助: 国家重点研发计划项目(2016YFC1303800)。
通讯作者:
▲通讯作者
[1] Boffetta P,Boccia S,Vecchia CL. A quick guide to cancer epidemiology [M]. Springer Int Publishing,2014,35(2):11-14.
[2] Zappa C,Mousa SA. Non-small cell lung cancer:current treatment and future advances [J]. Transl Lung Cancer Res,2016,5(3):288-300.
[3] Ostrem JM,Peters U,Sos ML,et al. KRAS(G12C)inhibitors allosterically control GTP affinity and effector interactions [J]. Nature,2013,503(7477):548-551.
[4] Lim SM,Westover KD,Ficarro SB,et al. Therapeutic targeting of oncogenic KRAS by a covalent catalytic site inhibitor [J]. Angew Chem Int Ed Engl,2014,53(1):199-204.
[5] Lobell RB,Liu D,Buser CA,et al. Preclinical and clinical pharmacodynamic assessment of L-778,123,a dual inhibitor of farnesyl:protein transferase and geranylgeranyl:protein transferase type-Ⅰ [J]. Mol Cancer Ther,2002,1(1):747-758.
[6] Basso AD,Kirschmeier P,Bishop WR. Thematic review series:lipid posttranslational modifications. Farnesyl transferase inhibitors [J]. J Lipid Res,2006,47(1):15-31.
[7] Tomasini P,Walia P,Labbe C,et al. Targeting the KRAS pathway in non-small cell lung cancer [J]. Oncologist,2016, 21(12):1-11.
[8] Bosse T,terHaar NT,Seeber LM,et al. Loss of ARID1A expression and its relationship with PI3K-Akt pathway alterations,TP53 and microsatellite instability in endometrial cancer [J]. Mod Pathol,2013,26(11):1525-1535.
[9] Mashima T,Ushijima M,Matsuura M,et al. Comprehensive transcriptomic analysis of molecularly targeted drugs in cancer for target pathway evaluation [J]. Cancer Sci,2015, 106(7):909-920.
[10] Litvak AM,Paik PK,Woo KM,et al. Clinical characteristics and course of 63 patients with BRAF mutant lung cancers [J]. J Thorac Oncol,2014,9(11):1669-1674.
[11] Sosman JA,Johnson DB. Clinical utility of BRAF targeted therapy in melanoma [J]. Cancer Drug Discovery Development,2015,82(6):67-84.
[12] Hauschild A,Grob JJ,Demidov LV,et al. Dabrafenib in BRAF mutated metastatic melanoma:a multicentre,open-label,phase 3 randomised controlled trial [J]. Lancet,2012, 380(9839):358-365.
[13] Planchard D,Mazieres J,Riely GJ,et al. Interim results of phase Ⅱ study BRF113928 of dabrafenib in BRAF V600E mutation-positive non-small cell lung cancer (NSCLC) patients [J]. J Clin Oncol,2013,44(1):114-143.
[14] Planchard D,Besse B,Groen HJM,et al. Dabrafenib plus trametinib in patients with previously treated BRAF V600E mutant metastatic non-small cell lung cancer:an open-label,multicentre phase 2 trial [J]. Lancet Oncol,2016,17(7):984-993.
[15] Wislez M,Spencer ML,Izzo JG,et al. Inhibition of mammalian target of rapamycin reverses alveolar epithelial neoplasia induced by oncogenic KRAS [J]. Cancer Res,2005,65(8):3226-3235.
[16] Riely GJ,Brahmer JR,Planchard D,et al. Arandomized discontinuation phase Ⅱ trial of ridaforolimusin non-small cell lung cancer (NSCLC) patients with KRAS mutations [J]. J Clin Oncol,2012,30(suppl):7531a.
[17] Schubbert S,Shannon K,Bollag G. Hyperactive RAS in developmental disorders and cancer [J]. Nat Rev Cancer,2007,7(4):295-308.
[18] J?覿nne PA,Shaw AT,Pereira JR,et al. Selumetinib plus docetaxel for KRAS-mutant advanced non-small cell lung cancer:a randomised,multicentre,placebo-controlled,phase 2 study [J]. Lancet Oncol,2013,14(1):38-47.
[19] J?覿nne PA,Mann H,Ghiorghiu D. Study design and rationale for a randomized,placebo-controlled,double-blind study to assess the efficacy and safety of selumetinib in combination with docetaxel as second-line treatment in patients with KRAS-mutant advanced non-small cell lung cancer (SELECT-1) [J]. Clin Lung Cancer,2016, 17(2):e1-e4.
[20] J?覿nne P A,Smith I,Mcwalter G,et al. Impact of KRAS codon subtypes from a randomised phase Ⅱ trial of selumetinib plus docetaxel in KRAS mutant advanced non-small cell lung cancer [J]. Br J Cancer,2015,113(2):199-203.
[21] Vicent S,Chen R,Sayles LC,et al. Wilms tumor 1(WT1)regulates KRAS driven oncogenesis and senescence in mouse and human models [J]. J Clin Invest,2010, 120(11):3940-3952.
[22] Kumar MS,Hancock DC,Molina-Arcas M,et al. The GATA2 transcriptional network is requisite for RAS oncogene driven non-small cell lung cancer [J]. Cell,2012, 149(3):642-655.
[23] Litvak AM,Drilon AE,Rekhtman N,et al. Phase Ⅱ trial of bortezomib in KRAS G12D mutant lung cancers [J]. J Clin Oncol,2015,33(16):161-171.
[24] Puyol M,Martín A,Dubus P,et al. A synthetic lethal interaction between KRAS oncogenes and CDK4 unveils a therapeutic strategy for non-small cell lung carcinoma [J]. Cancer Cell,2010,18(6):63-73.
[25] Mao CQ,Xiong MH,Liu Y,et al. Synthetic lethal therapy for KRAS mutant non-small cell lung carcinoma with nanoparticle-mediated CDK4 siRNA delivery [J]. Mol Ther,2014,22(5):964-973.
[26] Squist LV,von Pawel J,Garmey EG,et al. Randomized phase Ⅱ study of erlotinib plustivantinib versus erlotinib plus placebo in previously treated non-small cell lung cancer [J]. J Clin Oncol,2011,29(24):3307-3315.
[27] Spigel DR,Ervin TJ,Ramlau RA,et al. Randomized phase Ⅱ trial of Onartuzumab in combination with erlotinib in patients with advanced non-small cell lung cancer [J]. J Clin Oncol,2013,31(32):4105-4114.
[28] Acquaviva J,Smith DL,Sang J,et al. Targeting KRAS mutant non-small cell lung cancer with the Hsp90 inhibitor ganetespib [J]. Mol Cancer Ther,2012,11(2):2633-2643.
[29] Gerber DE,Ramalingam SS,Morgensztern D,et al. A phase 2 study of defactinib(VS-6063),a cancer stem cell inhibitor that acts through inhibition of focal adhesion kinase(FAK),in patients with KRAS-mutant non-small cell lung cancer [J]. J Clin Oncol,2014,20(6):852-863.
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