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KRAS 突变结直肠癌相关治疗的研究进展Research progress in the related treatment of
KRAS mutant colorectal cancer- 中国癌症杂志 2024年34卷第10期 页码：979-986
- 作者机构：
1. 海军军医大学第一附属医院肛肠外科，上海 200433
2. 海军军医大学第一附属医院肿瘤科，上海 200433
- 作者简介：
[ "第一作者：张少华（ORCID: 0009-0009-5258-2368），硕士。" ]
郝立强（ORCID: 0000-0002-8122-7156），主任医师。
- 基金信息：
DOI：10.19401/j.cnki.1007-3639.2024.10.008
中图分类号： R735.3+4收稿：2024-04-27，
修回：2024-08-26，
纸质出版：2024-10-30
- 稿件说明：
移动端阅览
张少华, 黎哲宁, 王薇, 等.
KRAS 突变结直肠癌相关治疗的研究进展[J]. 中国癌症杂志, 2024,34(10):979-986.Shaohua ZHANG, Zhening LI, Wei WANG, et al. Research progress in the related treatment of
KRAS mutant colorectal cancer[J]. China Oncology, 2024, 34(10): 979-986.张少华, 黎哲宁, 王薇, 等.
KRAS 突变结直肠癌相关治疗的研究进展[J]. 中国癌症杂志, 2024,34(10):979-986. DOI： 10.19401/j.cnki.1007-3639.2024.10.008.Shaohua ZHANG, Zhening LI, Wei WANG, et al. Research progress in the related treatment of
KRAS mutant colorectal cancer[J]. China Oncology, 2024, 34(10): 979-986. DOI： 10.19401/j.cnki.1007-3639.2024.10.008.
摘要
Kirsten大鼠肉瘤病毒癌基因同源物（Kirsten rats arcomaviral oncogene homolog，
KRAS
）是一类与肿瘤关系密切的基因，其表达水平的高低是提示肿瘤患者预后、放化疗效果等的重要指标。
RAS
突变是人类肿瘤中最为常见的致癌驱动突变，其中
KRAS
突变占比高达85%。
KRAS
突变位置主要集中在第12、13、61、146位密码子。密码子G12作为4个热点中突变频率最高的密码子又分为多种亚型，其中G12D突变最常见，其次是G12V、G12C等。结直肠癌（colorectal cancer，CRC）是
KRAS
突变频率较高的肿瘤之一。G12D和G12V是CRC中常见的两种突变亚型。
KRAS
G12C
抑制剂上市之后，其他靶向治疗药物也相继进入临床试验阶段。本研究总结
KRAS
基因突变的结直肠癌临床研究领域的新进展，包括靶向治疗药物、化疗药物、免疫治疗药物、细胞毒类药物、铁死亡及其他治疗方法研究的最新进展等。其中，在靶向治疗药物方面，本综述探讨了
KRAS
G12C
抑制剂（sotorasib、adagrasib、D-1553、IBI351等）、抗血管生成药物（单克隆抗体如贝伐珠单抗、雷莫芦单抗等）、小分子多靶点酪氨酸激酶抑制剂如舒尼替尼等的临床应用。而在免疫治疗药物方面，亦有诸多进展，如ARETHUSA临床试验发现，替莫唑胺使O-6-甲基鸟嘌呤-DNA甲基转移酶（O-6-methylguanine-DNA methyltransferase，MGMT）缺失、
RAS
突变的晚期转移性结直肠癌（metastatic colorectal cancer，mCRC）患者的肿瘤突变负荷（tumor mutational burden，TMB）增大，为患者的免疫治疗提供了创新性思路；再如信迪利单抗联合贝伐珠单抗、奥沙利铂和卡培他滨可用于一线治疗
RAS
突变、微卫星稳定（microsatellite stability，MSS）、不可切除的mCRC。相关研究显示联合用药有较好的治疗潜力和可控的安全耐受性。本综述通过探讨
KRAS
突变的机制及临床研究及治疗的最新进展，以期为
KRAS
突变结直肠癌的治疗提供参考。
Abstract
Kirsten rat sarcoma viral oncogene homolog (
KRAS
) is a type of gene closely related to human tumors. And it’s an important medical index to access the tumor development
prognosis and the efficacy of chemoradiotherapy.
RAS
mutations
in which
KRAS
mutations account for up to 85%
are the most common oncogenic driving mutations in human tumors. The most frequent
KRAS
mutation sites are codons 12
13
61 and 146. Codon G12
as the most frequently mutated one
can be divided into multiple subtypes
with G12D mutation being the most common
followed by G12V
G12C
etc. Colorectal cancer (CRC) is one of the tumors with the highest frequency of
KRAS
mutations. Both G12D and G12V are the most common mutation subtypes in CRC. In the field of treatments for CRC with
KRAS
mutations
targeted therapy had not been possible until the release of
KRAS
G12C
inhibitors in 2013
and new drugs have been developed one after another since then. This study summarized the mutations of
KRAS
and the advances in clinical research
including the latest advances in targeted drugs
chemotherapy drugs
immunotherapy drugs
ferroptosis
and other treatment methods. Among them
in terms of targeted drugs
this review explored
KRAS
G12C
inhibitors (sotorasib
adagrasib
D-1553
IBI351
etc.)
anti-angiogenic drugs (monoclonal antibodies such as bevacizumab
remdesizumab
etc)
small molecule multi-target tyrosine kinase inhibitors such as sunitinib
etc. In terms of immunotherapy drugs
there have also been many advances
such as the ARETHUSA clinical trial
which found that temozolomide reduced the tumor mutational burden (TMB) of O-6-methylguanine-DNA methyltransferase (MGMT) deficiency and
RAS
mutation in patients with advanced metastatic colorectal cancer (mCRC)
providing innovative ideas for patient immunotherapy. For example
the combination of xindilimab with bevacizumab
oxaliplatin
and capecitabine can be used for first-line treatment of
RAS
mutations
microsatellite stability (MSS)
and unresectable mCRC. Relevant studies have shown that the combination therapy has good therapeutic potential and controllable tolerability safety. This review explored the mechanisms of
KRAS
mutations and the latest advances in clinical research and treatment
in order to provide reference for the treatment of
KRAS
mutated colorectal cancer.
关键词
Keywords
references
SIRAVEGNA G , MUSSOLIN B , BUSCARINO M , et al. Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients [J ] . Nat Med , 2015 , 21 ( 7 ): 827.
BEKAII-SAAB T S , YAEGER R , SPIRA A I , et al. Adagrasib in advanced solid tumors harboring a KRAS G12C mutation [J ] . J Clin Oncol , 2023 , 41 ( 25 ): 4097 - 4106 .
KAWAGUCHI Y , KOPETZ S , NEWHOOK T E , et al. Mutation status of RAS , TP 53, and SMAD 4 is superior to mutation status of RAS alone for predicting prognosis after resection of colorectal liver metastases [J ] . Clin Cancer Res , 2019 , 25 ( 19 ): 5843 - 5851 .
SHEN C J , CHAN R H , LIN B W , et al. Oleic acid-induced metastasis of KRAS / p 53-mutant colorectal cancer relies on concurrent KRAS activation and IL-8 expression bypassing EGFR activation [J ] . Theranostics , 2023 , 13 ( 13 ): 4650 - 4666 .
CANON J , REX K , SAIKI A Y , et al. The clinical KRAS (G 12 C) inhibitor AMG 510 drives anti-tumour immunity [J ] . Nature , 2019 , 575 ( 7781 ): 217 - 223 .
HONG D S , FAKIH M G , STRICKLER J H , et al. KRAS G12C inhibition with sotorasib in advanced solid tumors [J ] . N Engl J Med , 2020 , 383 ( 13 ): 1207 - 1217 .
FAKIH M G , SALVATORE L , ESAKI T , et al. Sotorasib plus panitumumab in refractory colorectal cancer with mutated KRAS G12C [J ] . N Engl J Med , 2023 , 389 ( 23 ): 2125 - 2139 .
OU S I , JÄNNE P A , LEAL T A , et al. First-in-human phase Ⅰ/ⅠB dose-finding study of adagrasib (MRTX849) in patients with advanced KRAS G12C solid tumors (KRYSTAL-1) [J ] . J Clin Oncol , 2022 , 40 ( 23 ): 2530 - 2538 .
YAEGER R , WEISS J , PELSTER M S , et al. Adagrasib with or without cetuximab in colorectal cancer with mutated KRAS G12C [J ] . N Engl J Med , 2023 , 388 ( 1 ): 44 - 54 .
FAKIH M G , KOPETZ S , KUBOKI Y , et al. Sotorasib for previously treated colorectal cancers with KRAS G12C mutation (CodeBreaK100): a prespecified analysis of a single-arm, phase 2 trial [J ] . Lancet Oncol , 2022 , 23 ( 1 ): 115 - 124 .
SACHER A , LORUSSO P , PATEL M R , et al. Single-agent divarasib (GDC-6036) in solid tumors with a KRAS G12C mutation [J ] . N Engl J Med , 2023 , 389 ( 8 ): 710 - 721 .
SHI Z , WENG J F , NIU H T , et al. D-1553: a novel KRAS G12C inhibitor with potent and selective cellular and in vivo antitumor activity [J ] . Cancer Sci , 2023 , 114 ( 7 ): 2951 - 2960 .
WANG J , MARTIN-ROMANO P , CASSIER P , et al. Phase Ⅰ study of JNJ-74699157 in patients with advanced solid tumors harboring the KRAS G12C mutation [J ] . Oncologist , 2022 , 27 ( 7 ): 536-e553.
LIANG X J , SHEN J . Impact of KRAS mutation status on outcomes of metastatic colorectal cancer treated with anti-angiogenic agents: a meta-analysis [J ] . J Chemother , 2020 , 32 ( 1 ): 41 - 48 .
CREMOLINI C , LOUPAKIS F , ANTONIOTTI C , et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study [J ] . Lancet Oncol , 2015 , 16 ( 13 ): 1306 - 1315 . DOI: 10.1016/S1470-2045(15)00122-9 http://doi.org/10.1016/S1470-2045(15)00122-9
SARTORE-BIANCHI A , PIETRANTONIO F , LONARDI S , et al. Circulating tumor DNA to guide rechallenge with panitumumab in metastatic colorectal cancer: the phase 2 CHRONOS trial [J ] . Nat Med , 2022 , 28 ( 8 ): 1612 - 1618 .
WANG F , HUANG Y S , WU H X , et al. Genomic temporal heterogeneity of circulating tumour DNA in unresectable metastatic colorectal cancer under first-line treatment [J ] . Gut , 2022 , 71 ( 7 ): 1340 - 1349 .
WU C , WILLIAMS T M , ROBB R , et al. Phase Ⅰ trial of trametinib with neoadjuvant chemoradiation in patients with locally advanced rectal cancer [J ] . Clin Cancer Res , 2020 , 26 ( 13 ): 3117 - 3125 .
GULAY K C M , ZHANG X L , PANTAZOPOULOU V , et al. Dual inhibition of KRAS G12D and pan-ERBB is synergistic in pancreatic ductal adenocarcinoma [J ] . Cancer Res , 2023 , 83 ( 18 ): 3001 - 3012 .
ZHOU C , LI W , SONG Z , et al. LBA33 A first-in-human phase Ⅰ study of a novel KRAS G12D inhibitor HRS-4642 in patients with advanced solid tumors harboring KRAS G12D mutation [J ] . Ann Oncol , 2023 , 34: S1273.
JIANG J J , JIANG L Y , MALDONATO B J , et al. Translational and therapeutic evaluation of RAS-GTP inhibition by RMC-6 236 in RAS -driven cancers [J ] . Cancer Discov , 2024 , 14 ( 6 ): 994 - 1017 .
KIM D , HERDEIS L , RUDOLPH D , et al. Pan- KRAS inhibitor disables oncogenic signalling and tumour growth [J ] . Nature , 2023 , 619 ( 7968 ): 160 - 166 .
XU J M , KIM T W , SHEN L , et al. Results of a randomized, double-blind, placebo-controlled, phase Ⅲ trial of trifluridine/tipiracil (TAS-102) monotherapy in Asian patients with previously treated metastatic colorectal cancer: the TERRA study [J ] . J Clin Oncol , 2018 , 36 ( 4 ): 350 - 358 .
YOSHINO T , VAN CUTSEM E , LI J , et al. Effect of KRAS codon 12 or 13 mutations on survival with trifluridine/tipiracil in pretreated metastatic colorectal cancer: a meta-analysis [J ] . ESMO Open , 2022 , 7 ( 3 ): 100511.
VAN DE HAAR J , MA X H , OOFT S N , et al. Codon-specific KRAS mutations predict survival benefit of trifluridine/tipiracil in metastatic colorectal cancer [J ] . Nat Med , 2023 , 29 ( 3 ): 605 - 614 .
WANG F , WANG ZX , CHEN G , et al. Expert opinions on immunotherapy for patients with colorectal cancer [J ] . Cancer Commun (Lond) , 2020 , 40 ( 10 ): 467 - 472 .
MULLARD A . 2020 FDA drug approvals [J ] . Nat Rev Drug Discov , 2021 , 20 ( 2 ): 85 - 90 . DOI: 10.1038/d41573-021-00002-0 http://doi.org/10.1038/d41573-021-00002-0
CRISAFULLI G , SARTORE-BIANCHI A , LAZZARI L , et al. Temozolomide treatment alters mismatch repair and boosts mutational burden in tumor and blood of colorectal cancer patients [J ] . Cancer Discov , 2022 , 12 ( 7 ): 1656 - 1675 . DOI: 10.1158/2159-8290.CD-21-1434 http://doi.org/10.1158/2159-8290.CD-21-1434
FANG X , ZHONG C , WENG S , et al. Sintilimab plus bevacizumab and CapeOx (BBCAPX) on first-line treatment in patients with RAS mutant, microsatellite stable, metastatic colorectal cancer: study protocol of a randomized, open-label, multicentric study [J ] . BMC Cancer , 2023 , 23 ( 1 ): 676.
WANG F , JIN Y , WANG M , et al. Combined anti-PD-1, HDAC inhibitor and anti-VEGF for MSS/pMMR colorectal cancer: a randomized phase 2 trial [J ] . Nat Med , 2024 , 30 ( 4 ): 1035 - 1043 . DOI: 10.1038/s41591-024-02813-1 http://doi.org/10.1038/s41591-024-02813-1
YAN H , TALTY R , JAIN A , et al. Discovery of decreased ferroptosis in male colorectal cancer patients with KRAS mutations [J ] . Redox Biol , 2023 , 62 : 102699 .
CHEN P , LI X J , ZHANG R N , et al. Combinative treatment of β-elemene and cetuximab is sensitive to KRAS mutant colorectal cancer cells by inducing ferroptosis and inhibiting epithelial-mesenchymal transformation [J ] . Theranostics , 2020 , 10 ( 11 ): 5107 - 5119 .
SINHA B K , BORTNER C D , JARMUSCH A K , et al. Ferroptosis-mediated cell death induced by NCX4040, the non-steroidal nitric oxide donor, in human colorectal cancer cells: Implications in therapy [J ] . Cells , 2023 , 12 ( 12 ): 1626.
ZHOU X H , KANG J , ZHANG L L , et al. Osthole inhibits malignant phenotypes and induces ferroptosis in KRAS -mutant colorectal cancer cells via suppressing AMPK/Akt signaling [J ] . Cancer Chemother Pharmacol , 2023 , 92 ( 2 ): 119 - 134 .
YANG J W , MO J J , DAI J J , et al. Cetuximab promotes RSL3-induced ferroptosis by suppressing the Nrf2/HO-1 signalling pathway in KRAS mutant colorectal cancer [J ] . Cell Death Dis , 2021 , 12 ( 11 ): 1079.
CUI W W , GUO M , LIU D , et al. Gut microbial metabolite facilitates colorectal cancer development via ferroptosis inhibition [J ] . Nat Cell Biol , 2024 , 26 ( 1 ): 124 - 137 . DOI: 10.1038/s41556-023-01314-6 http://doi.org/10.1038/s41556-023-01314-6
JIFFRY J , THAVORNWATANAYONG T , RAO D , et al. Oncolytic reovirus (pelareorep) induces autophagy in KRAS -mutated colorectal cancer [J ] . Clin Cancer Res , 2021 , 27 ( 3 ): 865 - 876 .
GOEL S , OCEAN A J , PARAKRAMA R Y , et al. Elucidation of pelareorep pharmacodynamics in a phase Ⅰ trial in patients with KRAS -mutated colorectal cancer [J ] . Mol Cancer Ther , 2020 , 19 ( 5 ): 1148 - 1156 .
YUN J , MULLARKY E , LU C Y , et al. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH [J ] . Science , 2015 , 350 ( 6266 ): 1391 - 1396 .
TANO M D , RAUCCI F , VERNIERI C , et al. Synergistic effect of fasting-mimicking diet and vitamin C against KRAS mutated cancers [J ] . Nat Commun , 2020 , 11 ( 1 ): 2332.
MAHDAVI NIYAKI Z , SALEHZADEH A , PEYMANI M , et al. Exploring the therapeutic potential of Fe 3 O 4 @Glu-oleuropein nanoparticles in targeting KRAS pathway-regulating lncRNAs in colorectal cancer cells [J ] . Biol Trace Elem Res , 2024 , 202 ( 7 ): 3073 - 3085 .
GOLDBERG S B , HERBST R S . The end of the beginning: progress and next steps in KRAS -mutant non-small cell lung cancer [J ] . Lancet , 2023 , 401 ( 10378 ): 706 - 707 .
DE LANGEN A J , JOHNSON M L , MAZIERES J , et al. Sotorasib versus docetaxel for previously treated non-small cell lung cancer with KRAS G12C mutation: a randomised, open-label, phase 3 trial [J ] . Lancet , 2023 , 401 ( 10378 ): 733 - 746 .
LI Z M , SONG Z B , ZHAO Y Q , et al. D-155 3 (garsorasib), a potent and selective inhibitor of KRAS G12C in patients with NSCLC: phase 1 study results [J ] . J Thorac Oncol , 2023 , 18 ( 7 ): 940 - 951 .
WONG C C , WU J L , JI F F , et al. The cholesterol uptake regulator PCSK9 promotes and is a therapeutic target in APC/ KRAS -mutant colorectal cancer [J ] . Nat Commun , 2022 , 13 ( 1 ): 3971.
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