Therapeutic strategies targeting the epidermal growth factor receptor signaling pathway in metastatic colorectal cancer

More than 1.9 million new colorectal cancer(CRC)cases and 935000 deaths were estimated to occur worldwide in 2020,representing about one in ten cancer cases and deaths.Overall,colorectal ranks third in incidence,but second in mortality.More than half of the patients are in advanced stages at diagnosis.Treatment options are complex because of the heterogeneity of the patient population,including different molecular subtypes.Treatments have included conventional fluorouracil-based chemotherapy,targeted therapy,immunotherapy,etc.In recent years,with the development of genetic testing technology,more and more targeted drugs have been applied to the treatment of CRC,which has further prolonged the survival of metastatic CRC patients.

新型KRAS^(G12C)抑制剂VT198的药效学及药动学研究

目的:通过细胞和小鼠模型实验研究新型KRAS^(G12C)抑制剂VT198的体内外抗肿瘤作用。建立VT198和其阳性对照药MRTX849的LC-MS/MS方法,研究VT198在大鼠体内的药动学特征。方法:运用CTG发光法、Transwell迁移实验检测VT198对KRAS^(G12C)突变的人非小细胞肺癌细胞NCI-H358增殖及迁移的影响。建造裸小鼠肿瘤细胞系移植模型,口服给药后测定荷瘤鼠的体重及肿瘤体积。灌胃(ig)给予SD大鼠VT198和其阳性对照药,建立LC-MS/MS方法测定大鼠血浆中的药物浓度,并计算药动学参数。结果:VT198的IC50为3.07 nmol·L^(-1),细胞迁移率为(36.39±1.87)%,体内肿瘤体积抑制率为124.56%。大鼠单次ig给药(剂量10 mg·kg^(-1))后,VT198的Tmax为(3.33±1.15)h,C_(max)为(627.67±102.94)ng·mL^(-1),AUC_(0-t)为(3805.33±1167.07)h·ng·mL^(-1),阳性对照药的T_(max)为(6.00±0.00)h,C_(max)为(69.63±18.11)ng·mL^(-1),AUC_(0-t)为(609.25±77.88)h·ng·mL^(-1)。结论:体外细胞实验表明VT198对NCI-H358细胞具有生长抑制及迁移抑制作用,体内药效学实验表明其能够有效抑制肿瘤体积增长,体内药动学实验表明VT198的吸收程度和速度优于阳性对照药MRTX849。VT198作为治疗KRAS^(G12C)突变蛋白相关癌症的潜在药物,具有进一步研究的价值。

Sotorasib对比多西他赛用于经治的KRAS^(G12C)突变晚期非小细胞肺癌:一项随机对照、开放标签、Ⅲ期临床研究

Sotorasib是一种特异性的、不可逆的GTPase蛋白KRAS^(G12C)抑制剂。CodeBreaK 200研究比较了Sotorasib与一种标准治疗方案在既往接受过其他抗肿瘤药物治疗的KRAS^(G12C)突变非小细胞肺癌(non-small cell lung cancer,NSCLC)患者中的疗效和安全性。研究者在22个国家的148个中心进行了一项随机、开放标签的Ⅲ期试验。该研究招募了年龄在18岁以上、既往含铂化疗和PD-1或PD-L1抑制剂治疗进展后的KRAS^(G12C)突变晚期NSCLC患者。关键的排除标准包括:出现新发或进展的未经治疗的脑部病变,或有症状的脑部病变、存在除KRAS^(G12C)以外的驱动基因突变(如EGFR或ALK)、既往接受过多西他赛治疗(若肿瘤在终止治疗后6个月内未进展,则允许使用多西他赛进行新辅助治疗或辅助治疗)、既往接受过KRAS^(G12C)抑制剂治疗、在研究第1天的前28天内接受过系统性抗肿瘤治疗,并在治疗开始2周内接受了治疗性或姑息性放疗。以开放标签的方式将入组患者随机1∶1分为Sotorasib口服组(960 mg,每日1次)和多西他赛静脉输注组(75 mg/m^(2),每3周1次),根据晚期疾病患者既往治疗线数(1 vs 2 vs>2)、种族(亚洲vs非亚洲)和中枢神经系统转移史(有vs无)进行分层。治疗持续到独立中心确认疾病进展、患者不耐受、开始另一种抗癌治疗、撤回同意或死亡,以先发生者为准。主要终点是无进展生存期,在意向治疗人群中通过盲态独立审阅中心进行评估,对所有接受治疗的患者进行安全性评估。该试验已在ClinicalTrials.gov注册(编号NCT04303780),目前仍处于有效状态,但不再招募患者。在2020年6月4日至2021年4月26日期间,345例患者被随机分配至Sotorasib组(n=171)或多西他赛组(n=174)。Sotorasib组和多西他赛组中各有169例(99%)和151例(87%)患者接受了至少一次剂量的治疗。在中位随访17.7(IQR:16.4~20.1)个月后,该研究达到了主要研究终点。与多西他赛组相比,Sotorasib组的无进展生存期显著性增加[5.6个月(95%CI:4.3~7.8)vs 4.5个月(95%CI:3.0~5.7);HR=0.66(95%CI:0.51~0.86);P=0.0017]。与多西他赛组相比,Sotorasib组耐受性良好,3级及以上(33%vs 40%)和严重的治疗相关不良事件(11%vs 23%)更少。Sotorasib最常见的3级或以上的治疗相关不良事件是腹泻(12%)、谷丙转氨酶升高(8%)和谷草转氨酶升高(5%);而对于多西他赛,最常见的3级或以上的治疗相关不良事件是中性粒细胞减少(9%)、疲劳(6%)和发热性中性粒细胞减少(5%)。相比较于多西他赛,Sotorasib显著性提高既往接受过其他抗肿瘤药物治疗的KRAS^(G12C)突变晚期NSCLC患者的无进展生存期,且具有更优的安全性。

氯胍增强索托拉西布抑制KRAS^(G12C)野生型膀胱癌细胞增殖和迁移的作用机制

目的:探讨氯胍能否增强KRAS^(G12C)野生型膀胱癌细胞对索托拉西布的敏感性及其作用机制。方法:使用MTT、克隆形成实验以及Compusyn软件检测索托拉西布与氯胍联用能否增强对KRAS^(G12C)野生型膀胱癌细胞增殖的抑制作用以及联用效果如何。划痕实验检测其对细胞迁移能力的抑制作用,WB实验检测其对增殖相关蛋白的抑制作用。结果:索托拉西布与氯胍联用能够增强对KRAS^(G12C)野生型膀胱癌细胞增殖与迁移的抑制作用,并且对增殖相关蛋白p-cRAF以及p-ERK等的表达抑制作用增强。结论:氯胍通过抑制RAF/ERK通路增强KRAS^(G12C)野生型膀胱癌细胞对索托拉西布的敏感性。

Covalent inhibitor targets KRas^(G12C):A new paradigm for drugging the undruggable and challenges ahead

KRAS is one of the most commonly mutated oncogenes in cancers and therapeutics directly targeting the KRas have been challenging.Among the different known mutants,KRas^(G12C) has been proved to be successfully targeted recently.Several covalent inhibitors selectively targeting KRas^(G12C) have shown promising efficacy against cancers harboring KRAS G12C mutation in clinical trials and AMG510(sotorasib)has been approved for the treatment of KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer.However,the overall responsive rate of KRas^(G12C) inhibitors was around 50%in patients with non-small cell lung cancer and the efficacy in patients with colorectal cancer or appendiceal cancer appears to be less desirable.It is of great importance to discover biomarkers to distinguish patients who are likely benefitted.Moreover,adaptive resistance would occur inevitably with the persistent administration like other molecularly targeted therapies.Several combinatorial regimens have been studied in an effort to potentiate the efficacy of KRas^(G12C) inhibitors in preclinical settings.This review summarized the recent progress of covalent KRas^(G12C) inhibitors with a focus on identifying biomarkers to predict or monitor the efficacy and proposing rational drug combinations based on elucidation of the mechanisms of drug resistance.

USH2A mutation and specific driver mutation subtypes are associated with clinical efficacy of immune checkpoint inhibitors in lung cancer

This study aimed to identify subtypes of genomic variants associated with the efficacy of immune checkpoint inhibitors(ICIs)by conducting systematic literature search in electronic databases up to May 31,2021.The main outcomes including overall survival(OS),progression-free survival(PFS),objective response rate(ORR),and durable clinical benefit(DCB)were correlated with tumor genomic features.A total of 1546 lung cancer patients with available genomic variation data were included from 14 studies.The Kirsten rat sarcoma viral oncogene homolog G12C(KRAS^(G12C))mutation combined with tumor protein P53(TP53)mutation revealed the promising efficacy of ICI therapy in these patients.Furthermore,patients with epidermal growth factor receptor(EGFR)classical activating mutations(including EGFRL858Rand EGFRΔ19)exhibited worse outcomes to ICIs in OS(adjusted hazard ratio(HR),1.40;95%confidence interval(CI),1.01-1.95;P=0.0411)and PFS(adjusted HR,1.98;95%CI,1.49-2.63;P<0.0001),while classical activating mutations with EGFR^(T790)Mshowed no difference compared to classical activating mutations without EGFR^(T790)Min OS(adjusted HR,0.96;95%CI,0.48-1.94;P=0.9157)or PFS(adjusted HR,0.72;95%CI,0.39-1.35;P=0.3050).Of note,for patients harboring the Usher syndrome type-2A(USH2A)missense mutation,correspondingly better outcomes were observed in OS(adjusted HR,0.52;95%CI,0.32-0.82;P=0.0077),PFS(adjusted HR,0.51;95%CI,0.38-0.69;P<0.0001),DCB(adjusted odds ratio(OR),4.74;95%CI,2.75-8.17;P<0.0001),and ORR(adjusted OR,3.45;95%CI,1.88-6.33;P<0.0001).Our findings indicated that,USH2A missense mutations and the KRAS^(G12C)mutation combined with TP53 mutation were associated with better efficacy and survival outcomes,but EGFR classical mutations irrespective of combination with EGFR^(T790)Mshowed the opposite role in the ICI therapy among lung cancer patients.Our findings might guide the selection of precise targets for effective immunotherapy in the clinic.

KRAS^(G12C)蛋白共价抑制剂的研究进展

Kirsten大鼠肉瘤病毒癌基因(KRAS)编码的一种小GTP酶是多条细胞信号通路中关键的调控蛋白,其12位甘氨酸突变为半胱氨酸(G12C)常导致细胞通路异常活化,这在肿瘤的发生发展中起着重要作用,而靶向KRAS^(G12C)蛋白的小分子共价抑制剂能够直接抑制由KRAS^(G12C)突变造成的细胞通路异常活化。本文就KRAS蛋白结构和功能及其G12C突变体的共价抑制剂的研发进展、面临的挑战及可能的解决方法进行综述,并对未来KRAS抑制剂的发展方向进行展望,旨在为该类抑制剂的研发提供有益的参考。

Apoptosis-inducing activity of synthetic hydrocarbon-stapled peptides in H358 cancer cells expressing KRAS^(G12C)

Lung cancers are the leading cause of cancer deaths worldwide and pose a grave threat to human life and health.Non-small cell lung cancer (NSCLC) is the most frequent malignancy occupying80%of all lung cancer subtypes.Except for other mutations (e.g.,KRAS^(G12V/D)) that are also vital for the occurrence,KRAS^(G12C) gene mutation is a significant driving force of NSCLC,with a prevalence of approximately 14% of all NSCLC patients.However,there are only a few therapeutic drugs targeting KRAS^(G12C) mutations currently.Here,we synthesized hydrocarbon-stapled peptide 3 that was much shorter and more stable with modest KRAS^(G12C) binding affinity and the same anti-tumor effect based on the a-helical peptide mimic SAH-SOS1_(A).The stapled peptide 3 effectively induced G2/M arrest and apoptosis,inhibiting cell growth in KRAS-mutated lung cancer cells via disrupting the KRASmediated RAF/MEK/ERK signaling,which was verified from the perspective of genomics and proteomics.Peptide 3 also exhibited strong anti-trypsin and anti-chymotrypsin abilities,as well as good plasma stability and human liver microsomal metabolic stability.Overall,peptide 3 retains the equivalent anti-tumor activity of SAH-SOS1_(A) but with improved stability and affinity,superior to SAH-SOS1_(A).Our work offers a structural optimization approach of KRAS^(G12C) peptide inhibitors for cancer therapy.

索托拉西布的临床研究进展

索托拉西布是KRAS^(G12C)突变变构调节剂,KRAS一度被认为不可成药靶标,索托拉西布的上市打破了这一僵局。它因特异性强,不良反应轻微等益处,在KRAS^(G12C)突变阳性的非小细胞肺癌患者的治疗过程中表现出较好的治疗效果,使患者中位无进展生存期得到延长。本文将从该药物化学理化性质、化学药理作用、化学作用机制、临床应用四个方面对其在KRAS^(G12C)突变阳性的非小细胞肺癌的研究进展进行论述。