鼠肉瘤病毒癌基因突变非小细胞肺癌靶向治疗研究进展

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摘要鼠肉瘤病毒癌基因（KRAS）突变是非小细胞肺癌中最常见的驱动基因突变之一，尽管在几十年前就已经发现KRAS 基因突变，但由于其独特的生物特性，靶向治疗KRAS 基因突变非小细胞肺癌一直面临瓶颈。然而新型KRAS G12C 抑制剂的面世打破了这一僵局，使KRAS 基因突变非小细胞肺癌靶向治疗得到进一步发展。目前国内外靶向KRAS 突变非小细胞肺癌的研究机制主要是抑制膜定位、直接抑制KRAS 基因、靶向抑制KRAS 下游信号及抑制KRAS 突变协同致死基因等。本综述概述KRAS 基因突变非小细胞肺癌靶向治疗的研究进展，以便于临床医师更加深入了解这一特殊类型非小细胞肺癌的靶向治疗。

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	戴南利
	向明钧
	杜维
	肖泽民

关键词 ：鼠肉瘤病毒癌基因突变, 鼠肉瘤病毒癌基因G12C 抑制剂, 非小细胞肺癌, 靶向治疗

Abstract：Kirsten rat sarcoma viral oncogene (KRAS) mutation is one of the most common driver gene mutations in non-small cell lung cancer.Although KRAS mutation was discovered decades ago,target therapy of non-small cells with KRAS mutations has been a bottleneck due to their unique biological characteristics.However, the emergence of new KRAS G12C inhibitors broke this deadlock and further developed targeted therapy for non-small cell lung cancer with mutations in the KRAS gene.The research mechanism of targeting KRAS mutant non-small cell lung cancer at home and abroad is mainly to inhibit membrane localization, directly inhibit KRAS gene, target inhibition of KRAS downstream signals, and inhibit KRAS mutation co-lethal genes.This review summarizes the research progress of targeted therapy for non-small cell lung cancer with mutations in the KRAS gene, so that clinicians can have a deeper understanding of targeted therapy for this particular type of non-small cell lung cancer.

Key words： Kirsten rat sarcoma viral oncogene mutation Kirsten rat sarcoma viral oncogene G12C inhibitors Nonsmall cell lung cancer Target therapy

基金资助:湖南省临床医疗技术创新引导项目（2018SK50 204）

引用本文:

戴南利；向明钧；杜维；肖泽民. 鼠肉瘤病毒癌基因突变非小细胞肺癌靶向治疗研究进展[J]. 中国当代医药, 2021, 28(10): 28-31转39.
DAI Nan-li； XIANG Ming-jun；DU Wei； XIAO Ze-min. Research progress on targeted therapy of Kirsten rat sarcoma virus oncogene mutation in non-small cell lung cancer. 中国当代医药, 2021, 28(10): 28-31转39.

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http://dangdaiyiyao.com/CN/ 或 http://dangdaiyiyao.com/CN/Y2021/V28/I10/28

[1]	Friedlaender A，Banna G，Malapelle U，et al.Next Generation Sequencing and Genetic Alterations in Squamous Cell Lung Carcinoma：Where Are We Today?[J].Front Oncol，2019，9：166.
[2]	Siegel RL，Miller KD，Jemal A.Cancer statistics，2020[J].CA Cancer J Clin，2020，70（1）：7-30.
[15]	Nagasaka M，Li Y，Sukari A，et al.KRAS G12C Game of Thrones，which direct KRAS inhibitor will claim the iron throne?[J].Cancer Treat Rev，2020，84：101974.
[20]	Yang H，Liang SQ，Schmid RA，et al.New Horizons in KRAS-Mutant Lung Cancer：Dawn After Darkness[J].Front Oncol，2019，9：953.
[3]	Friedlaender A，Drilon A，Weiss GJ，et al.KRAS as a druggable target in NSCLC：Rising like a phoenix after decades of development failures[J].Cancer Treat Rev，2020，85：101978.
[4]	Ghimessy A，Radeczky P，Laszlo V，et al.Current therapy of KRAS-mutant lung cancer[J].Cancer and Metastasis Rev，2020，39（4）：1159-1177.
[5]	Román M，Baraibar I，López I，et al.KRAS oncogene in non-small cell lung cancer：clinical perspectives on the treatment of an old target[J].Mol Cancer，2018，17（1）：33.
[6]	Santos E，Martin-Zanca D，Reddy EP，et al.Malignant activation of a K-ras oncogene in lung carcinoma but not in normal tissue of the same patient[J].Science，1984，223（4637）：661-664.
[7]	Wood K，Hensing T，Malik R，et al.Prognostic and Predictive Value in KRAS in Non-Small-Cell Lung Cancer：A Review[J].JAMA Oncol，2016，2（6）：805-812.
[8]	Garrido P，Olmedo ME，Gómez A，et al.Treating KRAS-mutant NSCLC：latest evidence and clinical consequences[J].Ther Adv Med Oncol，2017，9（9）：589-597.
[9]	Jia Y，Jiang T，Li X，et al.Characterization of distinct types of KRAS mutation and its impact on first-line platinum-based chemotherapy in Chinese patients with advanced non-small cell lung cancer[J].Oncol Lett，2017，14（6）：6525-6532.
[10]	Nussinov R，Jang H，Tsai CJ，et al.Intrinsic protein disorder in oncogenic KRAS signaling[J].Cell Mol Life Sci，2017，74（17）：3245-3261.
[11]	Adjei AA，Mauer A，Bruzek L，et al.Phase Ⅱstudy of the farnesyl transferase inhibitor R115777 in patients with advanced non-small-cell lung cancer[J].J Clin Oncol，2003，21（9）：1760-1766.
[12]	Riely GJ，Johnson ML，Medina C，et al.A phase Ⅱtrial of Salirasib in patients with lung adenocarcinomas with KRAS mutations[J].J Thorac Oncol，2011，6（8）：1435-1437.
[13]	Tomasini P，Walia P，Labbe C，et al.Targeting the KRAS Pathway in Non-Small Cell Lung Cancer[J].Oncologist，2016，21（12）：1450-1460.
[14]	Cox AD，Fesik SW，Kimmelman AC，et al.Drugging the undruggable RAS： Mission possible?[J].Nat Rev Drug Discov，2014，13（11）：828-851.
[16]	Janes MR，Zhang J，Li LS，et al.Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor[J].Cell，2018，172（3）：578-589.
[17]	Fakih M，O′Neil B，Price TJ，et al.Phase 1 study evaluating the safety，tolerability，pharmacokinetics（PK），and efficacy of AMG 510，a novel small molecule KRASG12C inhibitor，in advanced solid tumors[J].J Clin Oncol，2019，37：3003.
[18]	Jnne PA，Papadopoulous K，Ou I，et al.A Phase 1 clinical trial evaluating the pharmacokinetics（PK），safety，and clinical activity of MRTX849，a mutant-selective small molecule KRAS G12C inhibitor，in advanced solid tumors[C].AACRNCI-EORTC International Conference on Molecular Targets，Boston，America：2019.
[19]	Feng H，Zhang Y，Bos PH，et al.K-Ras G12D Has a Potential Allosteric Small Molecule Binding Site[J].Biochemistry，2019，58（21）：2542-2554.
[21]	Blasco RB，Francoz S，Santamaría D，et al.c-Raf，but not B-Raf，is essential for development of K-Ras oncogenedriven non-small cell lung carcinoma[J].Cancer Cell，2011，19（5）：652-663.
[22]	Terrell EM，Durrant DE，Ritt DA，et al.Distinct Binding Preferences between Ras and Raf Family Members and the Impact on Oncogenic Ras Signaling[J].Mol Cell，2019，76（6）：872-884.
[23]	Blasco MT，Navas C，Martín-Serrano G，et al.Complete Regression of Advanced Pancreatic Ductal Adenocarcinomas upon Combined Inhibition of EGFR and C-RAF[J].Cancer Cell，2019，35（4）：573-587.
[24]	Matikas A，Mistriotis D，Georgoulias V，et al.Targeting KRAS mutated non-small cell lung cancer：A history of failures and a future of hope for a diverse entity[J].Crit Rev Oncol Hematol，2017，110：1-12.
[25]	Jnne PA，Smith I，McWalter G，et al.Impact of KRAS codon subtypes from a randomised phase Ⅱtrial of selumetinib plus docetaxel in KRAS mutant advanced non-small-cell lung cancer[J].Br J Cancer，2015，113（2）：199-203.
[26]	Jnne PA，van den Heuvel MM，Barlesi F，et al.Selumetinib Plus Docetaxel Compared With Docetaxel Alone and Progression-Free Survival in Patients With KRAS-Mutant Advanced Non-Small Cell Lung Cancer：The SELECT -1 Randomized Clinical Trial[J].JAMA，2017，317（18）：1844-1853.
[27]	Blumenschein GR Jr，Smit EF，Planchard D，et al.A randomized phase Ⅱ study of the MEK1/MEK2 inhibitor trametinib（GSK1120212）comparedwithdocetaxelinKRASmutant advanced non-small-cell lung cancer（NSCLC）[J].Ann Oncol，2015，26（5）：894-901.
[28]	Aredo JV，Padda SK.Management of KRAS-Mutant Non-Small Cell Lung Cancer in the Era of Precision Medicine[J].Curr Treat Options Oncol，2018，19（8）：43.
[29]	Yamamoto N，Fujiwara Y，Tamura K，et al.Phase Ⅰa/Ⅰb study of the pan-class ⅠPI3K inhibitor pictilisib（GDC-0941） administered as a single agent in Japanese patients with solid tumors and in combination in Japanese patients with non-squamous non-small cell lung cancer[J].Invest New Drugs，2017，35（1）：37-46.
[30]	Vansteenkiste JF，Canon JL，De Braud F，et al.Safety and Efficacy of Buparlisib（BKM120） in Patients with PI3K Pathway-Activated Non-Small Cell Lung Cancer：Resultsfrom the Phase ⅡBASALT-1 Study[J].J Thorac Oncol，2015，10（9）：1319-1327.
[31]	Tan AC.Targeting the PI3K/Akt/mTOR pathway in nonsmall cell lung cancer（NSCLC）[J].Thorac Cancer，2020，11：511-518.
[32]	Riely G，Brahmer J，Planchard D，et al.A randomized discontinuation phase Ⅱtrial of ridaforolimus in non-small cell lung cancer（NSCLC）patients with KRAS mutations[J].J Clin Oncol，2012，30：7531.
[33]	Aguirre AJ，Hahn WC.Synthetic Lethal Vulnerabilities in KRAS-Mutant Cancers[J].Cold Spring Harb Perspect Med，2018，8（8）：a031518.
[34]	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.
[35]	Wu C，Wang S，Xu C，et al.WT 1 enhances proliferation and impedes apoptosis in KRAS mutant NSCLC via targeting cMyc[J].Cell Physiol Biochem，2015，35（2）：647-662.
[36]	Barbie DA，Tamayo P，Boehm JS，et al.Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1[J].Nature，2009，462（7269）：108-112.
[37]	Drilon A，Schoenfeld AJ，Arbour KC，et al.Exceptional responders with invasive mucinous adenocarcinomas：a phase 2 trial of bortezomib in patients with KRAS G12D-mutant lung cancers[J].Cold Spring Harb Mol Case Stud，2019，5（2）：a003665.
[38]	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.
[39]	Goldman JW，Mazieres J，Barlesi F，et al.A randomized phase 3 study of abemaciclib versus erlotinib in previously treated patients with stage ⅣNSCLC with KRAS mutation：JUNIPER[J].J Clin Oncol，2018，36（15）：9025.
[40]	Shapiro GI，Hilton J，Gandi L，et al.Abstract CT046：PhaseⅠdose escalation study of the CDK4/6 inhibitor palbociclib in combination with the MEK inhibitor PD-0325901 in patients with RAS mutant solid tumors[J].Cancer Res，2017，77：CT046.
[41]	Ramalingam S，Goss G，Rosell R，et al.A randomized phaseⅡstudy of ganetespib，a heat shock protein 90 inhibitor，in combination with docetaxel in second-line therapy of advanced non-small cell lung cancer（GALAXY-1）[J].Ann Oncol，2015，26（8）：1741-1748.
[42]	Felip E，Barlesi F，Besse B，et al.Phase 2 Study of the HSP-90 Inhibitor AUY922 in Previously Treated and Molecularly Defined Patients with Advanced Non-Small Cell Lung Cancer[J].J Thorac Oncol，2018，13（4）：576-584.