K-RASG12C小分子共价抑制剂的研究进展

Ras原癌基因的突变是人类癌症中最常见的激活突变,驱动人类30％肿瘤的发生与发展,因此人们一直希望能够研发出靶向RAS蛋白的抗肿瘤药物,但进展缓慢.直至最近两年,随着首个K-RASG12C共价抑制剂AMG-510进入临床试验,直接靶向RAS蛋白的药物研发才逐渐显露出希望的曙光.本文主要介绍K-RASG12C小分子共价抑...     

KRAS小分子抑制剂研究进展

约30%人类癌症与RAS突变有关。RAS家族有3种亚型,即KRAS,HRAS和NRAS。KRAS已成为人类癌症中最常出现突变的基因之一,在多种癌症如胰腺癌、肺癌和结肠癌等均发现KRAS蛋白被上调或被突变激活。多年来,针对KRAS突变抗癌药物的临床活性并不乐观。安进公司利用KRAS突变产生的半胱氨酸残基成功开发上市了共价抑制剂AMG510,使KRAS再次成为新药研发热点。本文以小分子与KRAS蛋白的相互作用模式为依据,将KRAS小分子抑制剂分为直接作用抑制剂和间接作用抑制剂,综述了各类抑制剂的代表结构、作用机制和生物活性研究进展,为KRAS小分子抑制剂抗肿瘤新药的开发提供思路和方向。     

KRAS抑制剂的研究进展

RAS (rat sarcoma)基因是一种重要的致癌基因,其突变存在于约30％的人类肿瘤中.KRAS (kirsten rat sarcoma viral oncogene)是RAS的三个亚型之一,且相比于其他两种RAS亚型更易出现突变.近年来,研究的不断深入为靶向KRAS治疗肿瘤提供了新的可能性,KRAS抑制剂的研...     

KRASG12C抑制剂抗肿瘤耐药机制及克服策略研究进展

KRAS是人类癌症中最常出现突变的致癌基因之一。尽管长期以来诸多研究致力于直接或间接靶向KRAS的干预策略研究,但仍面临难以靶向、效果受限的问题,因此KRAS一直被认为是“不可成药”的靶点蛋白。最近,KRAS^G12C突变亚型特异性抑制剂研究取得重大突破,部分KRAS^G12C抑制剂相继进入临床试验,包括阿达格拉西布(adagrasib)和索托拉西(sotorasib)等,且已显示出显著的疗效,为KRAS^G12C突变驱动的恶性肿瘤患者带来了希望。RAS通路其他抑制剂的研发经验表明,快速产生的耐药性会限制药物的作用,而目前研究已经发现KRAS^G12C抑制剂亦存在明显的耐药问题。本文概述KRAS^G12C抑制剂的研发现状,讨论其耐药的机制,为探索克服其耐药的干预策略提供思路和方向。     

KRAS及其抑制剂的研究进展

RAS是人类癌症中最常发生突变的致癌基因,而KRAS则是RAS家族中最常发生突变的亚型,其中多数为12位密码子的突变。突变之后的KRAS使细胞的生长、增殖不受控制,进而导致癌症的发生与发展。尽管经过了30多年的努力,但直接靶向KRAS活性位点的药物开发均以失败告终。由于KRAS与GTP的亲和力极强,同时细胞中GTP浓度较高,以至于使KRAS成为“不可成药”靶点。近期,针对突变的KRAS G12C特异性共价抑制剂在临床试验中取得了突破性进展,为KRAS抑制剂的可成药性提供了临床证据。综述KRAS的结构功能及其小分子抑制剂的设计和临床研究概况,着重介绍具有代表意义的KRAS G12C抑制剂和其作为抗肿瘤药物的最新研发进展,为以KRAS为靶点的药物开发提供研究思路。     

SOS1蛋白在肿瘤发生中的作用及其抑制剂研究进展

RAS基因与胞内多条控制增殖、分化等生理过程的通路相关。RAS在肿瘤细胞中易突变,有KRAS、NRAS和HRAS这3种常见突变亚型。SOS1作为一种鸟嘌呤核苷酸交换因子,通过蛋白-蛋白相互作用激活RAS蛋白,因此SOS1抑制剂被认为可用于治疗RAS驱动的癌症。综述SOS1在肿瘤发生中的作用及其抑制剂的研究进展,旨在为以SOS1为靶点的药物开发提供思路。     

肿瘤KRAS基因突变靶向治疗研究进展

多数肿瘤伴随KRAS基因突变,并提示不良预后,靶向KRAS突变一直是临床肿瘤治疗的难点。突变的KRAS蛋白难以采用传统抑制活性位点的方式设计特异性抑制剂,被称为"不可靶向的药物靶点"。因此,探索靶向KRAS突变的药物策略成为了肿瘤药物研发的热点。虽然靶向KRAS治疗策略的研究进展有限,但鉴于对KRAS突变功能及恶性机制认识的不断深入,仍出现一些突破性的直接或间接抑制突变KRAS的新策略。该文就目前针对肿瘤KRAS基因突变的靶向治疗的研究进展进行综述,为KRAS突变肿瘤治疗提供新线索。     

治疗KRAS G12C突变非小细胞肺癌新药——Adagrasib

Adagrasib(研发代号:MRTX-849)是Mirati Therapeutics在研针对KRAS G12C突变的共价抑制剂,不可逆、选择性地与KRAS G12C位点共价结合,将其锁定在失活状态,达到治疗非小细胞肺癌(NSCLC)的目的。Adagrasib目前正在同步进行临床Ⅰ/Ⅱ/Ⅲ期试验,2021年6月,美国食品药品管理局授予Adagrasib"突破性疗法"资格认定,用于治疗KRAS G12C突变的NSCLC患者。本文主要针对Adagrasib的基本信息、作用机制、有效性及安全耐受性等方面作概述。     

针对分子靶点的抗肿瘤药物研究进展

随着肿瘤药理、分子药理学研究的飞速发展，针对分子靶点的抗肿瘤药物研发已成为当今抗肿瘤药物研究开发的重要方向。笔者综述了近年来DNA拓扑异构酶抑制剂、蛋白酪氨酸激酶抑制剂、肿瘤新生血管生成抑制剂、磷脂酰肌醇-3激酶／蛋白激酶B／哺乳动物雷帕霉素靶体（PI3K-AKT-mTOR）信号通路抑制剂、细胞周期依赖性蛋白激酶抑制剂的临床应用和临床研究进展。     

已上市K-RasG12C靶向药物的研发及其耐药性的最新研究进展

在多种类型癌症中KRAS发生突变,KRAS是人类癌症中最常见的突变癌基因。KRAS突变阳性癌症的发病人数一直呈上升趋势。由于KRAS缺乏经典的药物结合位点,导致靶向KRAS的抑制剂药物研发一直以来面临着巨大挑战性。随着K-Ras^G12C抑制剂的出现,KRAS不可成药的神话已被攻破。目前全球范围内上市的两种K-Ras^G12C抑制剂是AMG-510和MRTX849,仍然面临着巨大的用药需求。了解成功上市药物有利于更好地研发新药。本文针对两款上市K-Ras^G12C抑制剂的研究以及该靶点面临的耐药机制研究进行总结和讨论,并总结了K-Ras^G12C抑制剂与其他治疗方法联合治疗克服耐药性的方法。     

Targeting the undruggable KRAS:In vitro anticancer property of andrographolide and its semisynthetic analogues in pancreatic adenocarcinoma cell lines harbouring oncogenic mutant K-ras

OBJECTIVE To evaluate the anticancer activity of andrographolide(AGP)and its semisynthetic analogues(SRJ09and SRJ23)in pancreatic adenocarcinoma(PDAC)cell lines harbouring therapeutically highly relevant oncogenic K-ras glycine-12(KRAS-G12)mutant proteins.In a landmark publication,we revealed that AGP and its derivatives bind KRAS protein to inhibit RAS signaling PNAS,110:10201-06).This discovery prompted the initiation of this investigation.METHODS The cell growth inhibitory effect of the compounds on PDAC cell lines〔PANC-1(KRAS-G12D),Capan-2(KRAS-G12V),and MIA PaCa-2(KRASG12C)〕,was assessed by MTT assay.RESULTS In comparison with AGP and SRJ09,SRJ23 showed the greatest growth inhibition in all PDAC cell lines with mutant KRAS proteins.The inhibitory effect of SRJ23 on the cell growth was similar for all PDAC cell lines.AGP exerted selective growth inhibition against PANC-1(KRAS-G12D)cells,while the growth inhibition of SRJ09 was selective towards Capan-2(KRAS-G12V)cells.CONCLUSION AGP and SRJ09 showed selectivity for PDAC cell lines with specific KRAS mutations.This suggests the mutational status of KRAS protein and the structural features of these two compounds orchestrally determined the magnitude of cell growth inhibition in PDAC cell lines.The higher potency of SRJ23 implies it could be developed into an anticancer agent for the treatment of mutant KRAS-driven malignancies.To this end,efforts are in progress to derive new molecules from this compound for further improvement of potency.     

TCR-mimic antibody-drug conjugates targeting intracellular tumor-specific mutant antigen KRAS G12V mutation

Limited clinical application of antibody-drug conjugates (ADCs) targeting tumor associated antigens (TAAs) is usually caused by on-target off-tumor side effect. Tumor-specific mutant antigens (TSMAs) only expressed in tumor cells which are ideal targets for ADCs. In addition, intracellular somatic mutant proteins can be presented on the cell surface by human leukocyte antigen class I (HLA I)molecules forming tumor-specific peptide/HLA I complexes. KRAS G12V mutation frequently occurred in varied cancer and was verified as a promising target for cancer therapy. In this study, we generated two TCR-mimic antibody-drug conjugates (TCRm-ADCs), 2E8-MMAE and 2A5-MMAE, targeting KRAS G12V/HLA-A*0201 complex, which mediated specific antitumor activity in vitro and in vivo without obvious toxicity. Our findings are the first time validate the strategy of TCRm-ADCs targeting intracellular TSMAs, which improves the safety of antibody-based drugs and provides novel strategy for precision medicine in cancer therapy.     

KRAS相关信号通路与小分子抑制剂研究进展

KRAS基因属于Ras基因家族,其编码的KRAS蛋白通过激活下游信号通路参与细胞增殖、分化及凋亡等生命活动的调控。某些KRAS基因突变会引起KRAS蛋白过度表达和持续活化,进而过度激活下游信号通路,导致细胞不可控制地增殖恶变,最终造成组织癌变。寻找KRAS突变相关肿瘤的治疗策略一直是研究热点之一,然而KRAS蛋白突变体是公认的难靶蛋白之一,其直接作用靶点的小分子抑制剂的设计具有很大的挑战性,目前尚无相关药物批准上市。通过对KRAS蛋白结构与功能、相关信号通路和突变体在肿瘤发生发展中的作用,以及相关小分子抑制剂的突破性研究进展进行综述,为进一步研发KRAS突变肿瘤治疗药物提供参考。     

KRAS inhibition in metastatic colorectal cancer: An update

About half of colorectal cancers harbor mutations in the KRAS gene. The presence of these mutations is associated with worse prognosis and, until now, the absence of matched targeted therapy options. In this review, we discuss clinical efforts to target KRAS in colorectal cancer from studies of downstream inhibitors to recent direct inhibitors of KRAS^G12C and other KRAS mutants. Early clinical trial data, however, suggest more limited activity for these novel inhibitors in colorectal cancer compared to other cancer types, and we discuss the role of receptor tyrosine kinase signaling and parallel signaling pathways in modulating response to these inhibitors. We also review the effect of KRAS mutations on the tumor-immune microenvironment and efforts to induce an immune response against these tumors.     

Post-translational modification of KRAS: potential targets for cancer therapy

Aberrant activation of the RAS superfamily is one of the critical factors in carcinogenesis. Among them, KRAS is the most frequently mutated one which has inspired extensive studies for developing approaches to intervention. Although the cognition toward KRAS remains far from complete, mounting evidence suggests that a variety of post-translational modifications regulate its activation and localization. In this review, we summarize the regulatory mode of post-translational modifications on KRAS including prenylation, post-prenylation, palmitoylation, ubiquitination, phosphorylation, SUMOylation, acetylation, nitrosylation, etc. We also highlight the recent studies targeting these modifications having exhibited potent anti-tumor activities.     

KRAS突变型肺癌作用机制与治疗策略的最新进展

肺癌是全球最常见的恶性肿瘤之一,KRAS是肺癌发生基因突变的重要位点。由于KRAS突变亚型中常缺乏药理学药物靶向的口袋,KRAS突变位点一直被认为是“不可成药”的靶点。本文主要概括了KRAS突变型肺癌的作用机制和KRAS成药所面临的困难,并对KRAS突变的治疗策略和耐药机制的最新进展进行阐述。     

KRAS mutations predict response to EGFR inhibitors

Five antiepidermal growth factor receptor therapies have been approved for the treatment of solid tumors. However, response rates are relatively low. Several biomarkers that enrich for patients with tumors most likely to respond to these therapeutic agents have been identified. Mutations in the intermediate signal transduction pathway member KRAS also selects patients with tumors depending on signaling through this pathway. However, because KRAS acts downstream of the EGF receptor, somatic changes in this gene can be used as a marker to exclude patients unlikely to benefit from anti-EGFR therapy. Recent clinical data have provided substantial evidence that KRAS mutational status should be utilized as a diagnostic marker for predicting that response to anti-EGFR therapies in colorectal and non-small cell lung cancer.     

Clinical characterization of patients with metastatic colorectal cancer depending on the KRAS status

This retrospective study investigated the clinical characteristics of patients with metastatic colorectal cancer (mCRC) depending on the KRAS status, thereby differentiating KRAS exon 2 mutations in codon 12 versus codon 13. In total, 273 patients with mCRC receiving first-line therapy were analyzed. One hundred patients were treated within the FIRE-3 trial (FOLFIRI plus cetuximab or bevacizumab), 147 patients within the AIO KRK-0104 trial (cetuximab plus CAPIRI or CAPOX), and further 26 patients received therapy outside the study. Thirty-eight tumors with KRAS mutation in codon 13, 140 tumors with mutation in codon 12, and 95 tumors with KRAS wild type as a comparison were included in this analysis. Bivariate analyses demonstrated significant differences between KRAS wild-type, codon 12-mutated, and codon 13-mutated tumors with regard to synchronous lymph node metastasis (P=0.018), organ metastasis (76.8% vs. 65.9% vs. 89.5%, P=0.009), liver metastasis (89.5% vs. 78.2% vs. 92.1%, P=0.025), lung metastasis (29.5% vs. 42.9% vs. 50%, P=0.041), liver-only metastasis (48.4% vs. 28.8% vs. 28.9%, P=0.006), and metastases in two or more organs (49.5, 61.4, 71.1, P=0.047). Regression models indicated a significant impact of KRAS mutations in codon 12 versus codon 13 for synchronous organ and nodal metastasis (P=0.01, 0.03). This pooled analysis indicates that mCRC is a heterogeneous disease, which seems to be defined by KRAS mutations of the tumor. Compared with KRAS codon 12 mutations, codon 13-mutated mCRC presents as a more aggressive disease frequently associated with local and distant metastases at first diagnosis.