转移性结直肠癌抗EGFR治疗的耐药机制研究进展

以表皮生长因子受体（EGFR）作为特异靶点的单克隆抗体西妥昔单抗和帕尼单抗联合化疗是有效的治疗携带鼠类肉瘤病毒癌基因野生型转移性结直肠癌的方法，两者的运用显著改善了转移性结直肠癌患者的预后，是结直肠癌治疗发展过程中的里程碑。然而，大多患者会对抗EGFR治疗产生耐药而致病情进展。因此，对耐药机制的充分认识及探索尤为重要，将有助于为耐药后治疗策略的制定提供方向。随着对EGFR耐药机制的深入研究，我们发现多种生物标志物和途径均与抗EGFR治疗的耐药有关。本文将对转移性结直肠癌抗EGFR耐药机制作出概述。     

西妥昔单抗疗效预测指标的研究进展

西妥昔单抗（cetuximal）是一种抗表皮因子受体（epider-malgrowthfactorreceptor,EGFR）人／鼠嵌合型IgGl单克隆抗体。能够阻碍内源EGFR配体的结合,进而阻断受体的二聚化、酪氨酸激酶磷酸化及其信号转导从而抑制受体的功能。此外,西妥昔单抗还可以介导抗体依赖的细胞介导的细胞毒作用（Antibody—dependent cellular cytotoxicity;ADCC）靶向杀伤表达EGFR的肿瘤细胞。西妥昔单抗对许多种肿瘤均有效,并能够提高放化疗的敏感性。EGFR免疫组化阳性表达是最初进行西妥昔单抗治疗的患者入选标准,然而,     

FCGR多态性对单克隆抗体抗肿瘤治疗的疗效预测价值

抗体依赖细胞介导的细胞毒作用（ADCC）是单克隆抗体如西妥昔单抗,利妥昔单抗,曲妥珠单抗发挥抗肿瘤作用的主要机制。FCG受体（FCGR）主要在人白细胞上,在ADCC中发挥重要作用。单克隆抗体的疗效与FCGR多态性密切相关,其中FCGR2A（H131R）和FCGR3A（V158F）是主要的基因型。这篇文章对FCGR多态性对单克隆抗体在肿瘤患者中的疗效预测价值做一综述。     

西妥昔单抗联合伊立替康治疗奥沙利铂加5-FU/CF治疗失败的转移性结肠癌一例报告

西妥昔单抗（Cetuximab，商品名爱必妥），属于人鼠嵌合型IgG1单抗，作用于表皮生长因子受体（epidermal growth factor receptor，EGFR）。EGFR在肿瘤细胞的生长、侵袭、血管生成和转移中扮演着重要的角色^[1-2]。西妥昔单抗特异性靶向于EGFR及其异二聚体，阻止配体与EGFR的结合，进而阻断受体的二聚化、     

抗EGFR单抗治疗复发/转移性头颈部鳞状细胞癌临床共识（2021年版）

头颈部鳞状细胞癌（squamous cell carcinoma of the head and neck,SCCHN）是头颈部肿瘤最为常见的一种类型,其疾病负担较重。SCCHN患者中,90%以上高表达表皮生长因子受体（epidermal growth factor receptor,EGFR）,因此通过单克隆抗体特异性地与EGFR结合,是抑制EGFR信号转导的一种重要方法。目前多种基于EGFR受体及其通路相关的靶向药物中,西妥昔单抗是唯一疗效确切的药物,已于2020年2月在中国获批用于一线治疗复发/转移性SCCHN（recurrent/metastatic SCCHN,R/M SCCHN）,随着西妥昔单抗逐步应用于临床,中国晚期SCCHN患者整体的治疗模式将不断得到优化和提升。值得注意的是,虽然靶向和免疫药物在SCCHN的治疗中取得了很大的进展,但仍然存在很多挑战,其中西妥昔单抗治疗R/M SCCHN在EGFR检测、药物应用时机、联合方案和应用剂量以及不良反应管理等方面尚未达成共识。本共识就西妥昔单抗用于R/M SCCHN一线、二线以及联合免疫治疗时的疗效和安全性,结合文献及中国临床实践进行阐述,并对相关治疗方案予以推荐,希望对西妥昔单抗规范化治疗SCCHN患者及优化临床实践提供指导。经过多轮商议和探讨,共识小组的专家汇总出以下推荐意见。在分子检测方面,R/M SCCHN患者无需常规检测EGFR以指导临床实践,抗EGFR单克隆抗体通过抑制EGFR信号转导起到抗肿瘤作用。一线治疗中,对于铂类药物耐受患者,建议6个周期的西妥昔单抗联合顺铂75 mg/m ² ,5-FU 750 mg/m ² 治疗,疾病缓解或稳定后继续接受西妥昔单抗单药维持治疗至疾病进展;对于有5-FU治疗禁忌证、持续静脉输液不方便、二氢嘧啶脱氢酶（dihydropyrimidine dehydrogenase,DPD）缺乏症及治疗依从性差的患者,建议4个周期的西妥昔单抗联合铂类药物（顺铂75 mg/m ² ,每3周1次）+多西他赛（75 mg/m ² ,每3周1次）治疗,疾病缓解或稳定后继续接受西妥昔单抗单药维持治疗至疾病进展;对于铂类药物不耐受的患者,建议西妥昔单抗联合紫杉醇每周方案治疗,直至疾病进展;对于身体状况良好的老年患者,建议西妥昔单抗+卡铂+5-FU治疗6个周期后,使用西妥昔单抗维持治疗。多个临床研究和真实世界数据均显示,西妥昔单抗联合化疗一线治疗显示出一致的高客观缓解率（objective response rate,ORR）和生存获益。二线治疗中,对于一线含铂类药物化疗方案治疗失败的患者,建议西妥昔单抗单药治疗或联合紫杉醇每周方案治疗;对于一线免疫检查点抑制剂（immune checkpoint inhibitor,ICI）治疗失败的患者,建议西妥昔单抗联合化疗方案,其中联合药物应基于之前的药物暴露加以调整。安全性方面,西妥昔单抗治疗方案相关的常见不良事件包括皮肤反应、输液反应和电解质紊乱。多数皮肤反应是轻度的,可以通过预防措施加以控制,在西妥昔单抗停药或减少剂量后,这些不良反应通常会消失而无后遗症。输液反应可通过输注前预防、输注时及输注后密切监测和及时干预加以有效控制。与单纯化疗相比,西妥昔单抗治疗相关的不良反应通常耐受性良好并且可接受。此外,西妥昔单抗联合免疫治疗或新型靶向药物的应用正在探索中,未来将为R/M SCCHN患者带来更多选择。     

西妥昔单抗疗效预测指标的研究进展

西妥昔单抗(cetuximal)是一种抗表皮因子受体(epidermal growth factor receptor, EGFR)人/鼠嵌合型IgG1单克隆抗体.能够阻碍内源EGFR配体的结合,进而阻断受体的二聚化、酪氨酸激酶磷酸化及其信号转导从而抑制受体的功能.此外,西妥昔单抗还可以介导抗体依赖的细胞介导的细胞毒作用(Antibody-dependent cellular cytotoxicity;ADCC)靶向杀伤表达EGFR的肿瘤细胞.西妥昔单抗对许多种肿瘤均有效,并能够提高放化疗的敏感性.EGFR免疫组化阳性表达是最初进行西妥昔单抗治疗的患者入选标准,然而,部分患者并未从西妥昔单抗的治疗中获益.一些临床研究结果也证实EGFR免疫组化结果与EGFR单抗治疗疗效并不甚相关.因此这就需要进一步探讨西妥昔单抗治疗有效性的标记物.     

抗EGFR治疗在头颈部鳞癌中的研究进展

表皮生长因子受体(Epidermal growth factor receptor, EGFR)在头颈部鳞状细胞癌(Head and neck squamous cell carcinoma, HNSCC)的发生发展中发挥重要作用。EGFR作为一种生物标志物，参与多种信号通路，且在HNSCC中高表达。目前，一系列抗EGFR靶向治疗药物相继用于HNSCC的临床研究及治疗，包括西妥昔单抗、尼妥珠单抗和阿法替尼等。本文就HNSCC抗EGFR的治疗现状和研究进展作一综述，以期为药物选择及预后等提供参考。     

影响表皮生长因子受体靶向治疗的相关分子检测

近年来,肿瘤分子靶向治疗药物不断出现,其中表皮生长因子受体(epidermal growth factor receptor,EGFR)成为治疗的重要靶点.针对EGFR治疗的策略有两类,一类是作用于胞外配体结合区的单克隆抗体,如西妥昔单抗、帕尼单抗和尼妥珠单抗;另一类是胞内酪氨酸激酶抑制剂(tyrosine kinase inhibitors,TKI),如吉非替尼、埃罗替尼等.     

西妥昔单抗治疗非小细胞肺癌耐药机制的研究进展

目的:总结国内外关于西妥昔单抗治疗非小细胞肺癌中耐药机制的研究进展.方法:应用Medline、PubMed、EMBASE及中国生物医学文献数据库检索系统,以"西妥昔单抗、非小细胞肺癌、表皮生长因子受体及耐药机制"为关键词,检索1990-01-2010-02的相关文献.纳入标准: 1)EGFR旁路信号传导通路与西妥昔单抗抵抗的关系;2)非小细胞肺癌患者EGFR基因突变与西妥昔单抗耐药;3)EGFR下游信号转导通路的活化与西妥昔单抗抵抗的关系.根据纳入标准分析34篇文献.结果:由于表皮生长因子受体(EGFR)调节多种细胞功能,EGFR抑制剂西妥昔单抗耐药现象可能与多个传导通路紊乱有关,包括旁路信号途径的激活、受体突变、配体自分泌/旁分泌的产生以及下游信号蛋白的组成性活化.结论:目前对西妥昔单抗产生耐药的确切机制尚不明确,要想解决其耐药问题,进一步提高西妥昔单抗治疗非小细胞肺癌的疗效,尚需进行更多项进一步的临床和基础研究来加以证实.     

大肠癌治疗中EGFR耐药相关分子

随着医学分子生物学技术的发展和对大肠癌分子发病机制的深入研究,以表皮生长因子受体(epidermal growth factor receptor,EGFR)为靶点的分子靶向治疗在大肠癌的治疗中作用显著.其中,以西妥昔单抗和帕尼单抗为代表的抗EG-FR单抗为大肠癌患者带来了福音,EGFR过表达的患者对EGFR单抗治疗敏感、疗效显著,但无论近期疗效如何,患者最终都不可避免的产生耐药性及病情进展.因此,了解抗EGFR单抗耐药机制有利于指导大肠癌患者的临床治疗.     

Prognostic vs predictive molecular biomarkers in colorectal cancer: is KRAS and BRAF wild type status required for anti-EGFR therapy?

An important molecular target for metastatic CRC treatment is the epidermal growth factor receptor (EGFR). Many potential biomarkers predictive of response to anti-EGFR monoclonal antibodies (cetuximab and panitumumab) have been retrospectively evaluated, including EGFR activation markers and EGFR ligands activation markers. With regard to the "negative predictive factors" responsible for primary or intrinsic resistance to anti-EGFR antibodies a lot of data are now available. Among these, KRAS mutations have emerged as a major predictor of resistance to panitumumab or cetuximab in the clinical setting and several studies of patients receiving first and subsequent lines of treatment have shown that those with tumors carrying KRAS mutations do not respond to EGFR-targeted monoclonal antibodies or show any survival benefit from such treatments. The role of B-RAF mutations, mutually exclusive with KRAS mutations, in predicting resistance to anti-EGFR mAbs is not yet consolidated. It therefore appears that BRAF mutations may play a strong negative prognostic role and only a slight role in resistance to anti-EGFR Abs.     

Epidermal growth factor receptor mutation mediates cross-resistance to panitumumab and cetuximab in gastrointestinal cancer

Acquired resistance to epidermal growth factor receptor (EGFR) targeted antibodies represents a clinical challenge in the treatment of gastrointestinal tumors such as metastatic colorectal cancer, but its molecular mechanisms are incompletely understood. We scanned KRAS exon 2/3/4, NRAS exon 2/3/4 and the overlapping epitopes of the EGFR antibodies cetuximab and panitumumab for mutations in pre- and post-treatment tumor tissue of 21 patients with gastrointestinal cancer treated with chemotherapy +/− EGFR antibodies by next-generation sequencing (“tumor tissue” cohort). We describe a novel EGFR exon 12 mutation acquired in tumors of 1 out of 3 patients treated with panitumumab. The EGFR G465R mutation introduces a positive charge within the overlap of the panitumumab and cetuximab epitopes. It abrogates antibody binding and mediates cross-resistance to both antibodies in EGFR G465R-transfected Ba/F3 cells. In circulating tumor DNA from an independent “liquid biopsy” cohort of 27 patients, we found this novel mutation in 1 out of 6 panitumumab-treated cases while about one third of patients show acquired RAS mutations. We show that acquired resistance by epitope-changing mutations also emerges during panitumumab treatment, which can be easily detected by a liquid biopsy approach even before clinical resistance occurs and this may help in tailoring EGFR-targeted therapies.     

Functional Dissection of the Epidermal Growth Factor Receptor Epitopes Targeted by Panitumumab and Cetuximab

Cetuximab and panitumumab, two antibodies targeting the extracellular domain of the epidermal growth factor receptor (EGFR), are of major clinical importance particularly in the treatment of metastatic colorectal cancer. As patients may acquire resistance-mediating mutations within the extracellular EGFR domain, functional dissection of the exact binding sites of EGFR targeting antibodies may help predict treatment responses. We therefore assessed the epitope recognition of panitumumab by screening phage-displayed random cyclic 7mer and linear 12mer peptide libraries on this antibody. Phage screenings revealed two strong, potentially epitope-mimicking consensus motifs targeted by panitumumab. A computational approach was used to map the sequences back to the potential epitope region on domain III of EGFR. The presumed epitope regions (386)WPEXRT(391) and a biochemically similar though discontinuous region P349-F352-D355 on a neighboring loop of domain III could be confirmed as part of the functionally relevant binding site of panitumumab by site-directed mutational analysis. To more accurately differentiate the panitumumab epitope from the previously characterized cetuximab epitope, binding studies were performed on a broad range of additional mutants. Taken together, this analysis revealed two large, partially overlapping functional epitopes consisting of 17 critical amino acid positions. Four of these positions were selectively targeted by cetuximab (I467, S468, Q408, and H409), whereas another four were selectively recognized by panitumumab (W386, E388, R390, and T391). In view of the clinical significance of extracellular domain mutations, our data may help guide treatment decisions in selected patients receiving EGFR-targeted therapies.     

In vitro elimination of epidermal growth factor receptor-overexpressing cancer cells by CD32A-chimeric receptor T cells in combination with cetuximab or panitumumab

Cetuximab and panitumumab bind the human epidermal growth factor receptor (EGFR). Although the chimeric cetuximab (IgG1) triggers antibody-dependent-cellular-cytotoxicity (ADCC) of EGFR positive target cells, panitumumab (a human IgG2) does not. The inability of panitumumab to trigger ADCC reflects the poor binding affinity of human IgG2 Fc for the FcγRIII (CD16) on natural killer (NK) cells. However, both human IgG1 and IgG2 bind the FcγRII (CD32A) to a similar extent. Our study compares the ability of T cells, engineered with a novel low-affinity CD32A^131R-chimeric receptor (CR), and those engineered with the low-affinity CD16^158F-CR T cells, in eliminating EGFR positive epithelial cancer cells (ECCs) in combination with cetuximab or panitumumab. After T-cell transduction, the percentage of CD32A^131R-CR T cells was 74 ± 10%, whereas the percentage of CD16^158F-CR T cells was 46 ± 15%. Only CD32A^131R-CR T cells bound panitumumab. CD32A^131R-CR T cells combined with the mAb 8.26 (anti-CD32) and CD16^158F-CR T cells combined with the mAb 3g8 (anti-CD16) eliminated colorectal carcinoma (CRC), HCT116^FcγR+ cells, in a reverse ADCC assay in vitro. Crosslinking of CD32A^131R-CR on T cells by cetuximab or panitumumab and CD16^158F-CR T cells by cetuximab induced elimination of triple negative breast cancer (TNBC) MDA-MB-468 cells, and the secretion of interferon gamma and tumor necrosis factor alpha. Neither cetuximab nor panitumumab induced Fcγ-CR T antitumor activity against Kirsten rat sarcoma (KRAS)-mutated HCT116, nonsmall-cell-lung-cancer, A549 and TNBC, MDA-MB-231 cells. The ADCC of Fcγ-CR T cells was associated with the overexpression of EGFR on ECCs. In conclusion, CD32A^131R-CR T cells are efficiently redirected by cetuximab or panitumumab against breast cancer cells overexpressing EGFR.     

生物标记物在转移性结直肠癌的抗EGFR治疗中的预测作用

目前,在肿瘤的治疗中EGFR信号通路成为重要的靶点,尤其在转移性结直肠癌(mCRC)的治疗中.EGFR单克隆抗体(mAbs)包括西妥昔单抗和帕尼单抗,抗EGFR mAbs联合传统的化疗在很大程度上改善了mCRC患者的无进展生存期(PFS)和总生存期(OS).然而,抗EGFR mAbs仅仅对KRAS野生型的mCRC患者有效,说明还有其他方面的因素影响着抗EGFR mAbs的疗效.研究表明,在结直肠癌中KRAS野生型(WT)的患者常伴有BRAF、PIK3A、NRAS突变和PTEN缺失,这些分子基因状态的改变可能与抗EGFR单克隆抗体靶向治疗抵抗性相关.因此检测患者对抗EGFR mAbs靶向治疗的相关生物标记物,可以对mCRC患者个体化治疗提供依据.     

Treatment with panitumumab after a severe infusion reaction to cetuximab in a patient with metastatic colorectal cancer: a case report

Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR) are effective in the treatment of metastatic colorectal cancer. Cetuximab is a human-murine chimeric monoclonal antibody targeting the EGFR. Even with premedication, cetuximab can result in an infusion reaction in select patients. In a portion of these patients, the reaction is severe, and further therapy with cetuximab is contraindicated, thus preventing these patients from receiving potentially beneficial anti-EGFR therapy. Panitumumab is a fully human monoclonal antibody also targeting the EGFR. Panitumumab is given without premedication and, in clinical trials, has rarely been associated with infusion reactions. It is not yet known whether panitumumab can be safely given in patients with a previous severe reaction to cetuximab. We report a case of a patient successfully treated with panitumumab after the patient had a severe infusion reaction to cetuximab.     

A review of cutaneous toxicities from targeted therapies in the treatment of colorectal cancers

Currently there are three targeted therapies approved for the treatment of colorectal cancers. These include the epidermal growth factor receptor (EGFR) inhibitors, cetuximab and panitumumab, and the multikinase inhibitor regorafenib. It is important to understand and recognize the common presentations of cutaneous toxicity that result from these agents to effectively manage symptoms and prevent premature discontinuation of anticancer treatment.Key Words: Cetuximab, panitumumab, regorafenibCurrently there are three targeted therapies approved for the treatment of colorectal cancers. These include the epidermal growth factor receptor (EGFR) inhibitors, cetuximab and panitumumab, and the multikinase inhibitor regorafenib. It is important to understand and recognize the common presentations of cutaneous toxicity that result from these agents to effectively manage symptoms and prevent premature discontinuation of anticancer treatment.     

Anti–Epidermal Growth Factor Receptor Monotherapy in the Treatment of Metastatic Colorectal Cancer: Where Are We Today?

Over the past 10 years there has been a significant increase in the armamentarium of agents available for use in the treatment of advanced colorectal cancer (CRC). Among these new agents are two monoclonal antibodies targeting the epidermal growth factor receptor (EGFR): cetuximab, a mouse–human chimeric monoclonal antibody, and panitumumab, a fully human monoclonal antibody. Both are approved as monotherapy for the treatment of chemotherapy‐refractory advanced CRC. Cetuximab is also indicated for use in combination with irinotecan. Here, we review 10 reports of phase II and III clinical studies of patients treated with panitumumab or cetuximab monotherapy. The clinical trials demonstrate similar efficacy profiles for advanced CRC patients treated with panitumumab and cetuximab monotherapy, with some differences in their adverse event profiles. In addition, the recent results of retrospective tumor KRAS gene mutational analyses in CRC patients treated with anti‐EGFR monotherapy are reviewed. Data from the clinical trials reviewed here clearly demonstrate that anti‐EGFR monotherapy is an effective treatment modality for patients with chemotherapy‐refractory advanced CRC.     

Clinical use of monoclonal antibodies to the epidermal growth factor receptor in colorectal cancer

Monoclonal antibodies to the epidermal growth factor receptor (EGFR) are among the promising novel targeted therapies being explored in colorectal cancer. Two such agents that inhibit EGFR signaling by interfering with ligand-binding are cetuximab (Erbitux) and panitumumab (Vectibix). This review will address the use of cetuximab and panitumumab in chemotherapy-refractory colorectal cancer as well as in front-line therapy for the disease, consider predictors of response and resistance, and outline comparisons between these agents.     

Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study

BACKGROUND: The antiepidermal growth factor receptor (antiEGFR) monoclonal antibodies cetuximab and panitumumab have good clinical activity in about 10% of patients with metastatic colorectal cancer that is resistant to chemotherapy. The molecular mechanisms underlying clinical response or resistance to these agents are unknown. METHODS: Tumours from 31 patients with metastatic colorectal cancer who had either an objective response (n=10) or stable disease or progressive disease (n=21) after treatment with cetuximab or panitumumab were screened for genetic changes in EGFR or its immediate intracellular effectors. Specifically, we assessed the EGFR copy number and the mutation profile of the EGFR catalytic domain and of selected exons in KRAS, BRAF, and PIK3CA. RESULTS: Eight of nine of patients with objective responses who were assessable by fluorescence in-situ hybridisation (FISH) had an increased EGFR copy number. By contrast, one of 21 non-responders assessable by FISH had an increased EGFR copy number (p<0.0001 for responders vs non-responders, Fisher's exact test). The mutation status of the EGFR catalytic domain and its immediate downstream effectors PIK3CA, KRAS, and BRAF did not correlate with disease response. In colorectal-cancer cell lines, the concentration of cetuximab that completely inhibited proliferation of cells with amplified EGFR copy number did not affect proliferation of cells with unamplified EGFR. INTERPRETATION: We propose that the response to antiEGFR treatment has a genetic basis and suggest that patients might be selected for treatment on the basis of EGFR copy number.