Combating Cetuximab Resistance in Colorectal Cancer

对抗结直肠癌中的西妥昔单抗耐药性

• 批准号: 9891024
• 负责人: YUESHENG ZHANG
• 金额: $ 40.07万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9891024
• 关键词: Address; Adverse effects; Affinity; Anticoagulants; BRAF gene; Binding; Cancer Model; Cell Culture Techniques; Cell Line; Cell Surface Receptors; Cells; Cetuximab; Clinical; Coagulation Process; Collagen; Colorectal Cancer; Data; Development; Dimerization; Dipeptidases; ERBB2 gene; Endocytosis; Enoxaparin; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; ErbB4 gene; Extracellular Domain; Family member; Foundations; Goals; Heterodimerization; Human; In Vitro; KRAS2 gene; Ligand Binding; Malignant Neoplasms; Medical; Metabolism; Modeling; Monoclonal Antibodies; Mus; Mutate; Mutation; Normal Cell; Oncogenic; Outcome; PIK3CA gene; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Phosphorylation; Play; Proteins; Publishing; Receptor Protein-Tyrosine Kinases; Recombinants; Research; Resistance; Role; Signal Transduction; Signaling Molecule; Signaling Protein; Small Interfering RNA; Solid; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Tyrosine Kinase Inhibitor; Xaa-Pro dipeptidase; Xenograft Model; base; cancer cell; cancer type; clinical efficacy; colon cancer cell line; colorectal cancer treatment; combat; gain of function mutation; hypoxia inducible factor 1; in vivo; knock-down; member; mutant; novel; overexpression; panitumumab; receptor binding; research clinical testing; response; targeted agent; therapeutic target; tool; translational study; tumor

Epidermal growth factor receptor (EGFR), an oncogenic receptor tyrosine kinase, is a major therapeutic target in several types of cancers. Two EGFR monoclonal antibodies (mAbs) are used to treat EGFR- positive colorectal cancer (CRC), including cetuximab (CTX) and panitumumab, which have the same mechanism of action. Unfortunately, primary and acquired resistance to the mAbs is very common: response in only 10-20% patients and lasts typically for 3-12 months. Current approach to combating the resistance is to combine the mAb with agent(s) that targets compensatory or altered downstream signaling molecules (ErbB2, cMET, KRAS, BRAF and PIK3CA), but clinical efficacy of such approach is uncertain. Importantly, we found that hPEPDG278D, a recombinant enzymatically inactive mutant of human peptidase D, strongly inhibits the proliferation of all tested CTX-resistant CRC cell lines, and silences EGFR, ErbB2 and their downstream signaling molecules in these cells. Our results suggest that EGFR and ErbB2 are pivotal therapeutic targets in CTX-resistant CRC cells. We recently showed: a) hPEPDG278D specifically binds to the extracellular domain of EGFR and ErbB2, disrupts their signaling units and directs them for degradation via endocytosis, and therefore is a novel dual inhibitor of EGFR and ErbB2; b) it selectively inhibits cancer cells overexpressing EGFR and/or ErbB2 in vitro and in vivo; c) it does not show toxicities in mouse studies. The goal of our proposal is to further evaluate hPEPDG278D for overcoming CTX resistance and to substantiate the novel concept that EGFR and ErbB2 remain critical therapeutic targets in CTX-resistant CRC cells. We hypothesize that hPEPDG278D overcomes CTX resistance by suppressing both ErbB2 and CTX-insensitive EGFR, and propose three Aims to test the hypothesis. Aim 1 is to determine the therapeutic efficacy of hPEPDG278D against CTX-resistant CRC tumors in vivo, using both orthotoptic tumor models and patient- derived xenograft models. Oncogenic ErbB3 and ErbB4 (other EGFR members) as well as cMET are also implicated in CTX resistance in CRC. Aim 2 is to investigate whether hPEPDG278D indirectly suppresses ErbB3, ErbB4 and cMET by disrupting their heterodimerization with EGFR or ErbB2, using both cell lines and treated tumors from Aim 1. Besides targeting ErbB2, hPEPDG278D also targets both CTX-sensitive and -insensitive EGFR. Aim 3 is to determine the mechanisms by which hPEPDG278D targets CTX-insensitive (mutated or wild type) EGFR in relevant CRC cell lines. In summary, it is a widely accepted concept in the field that CRC resistance to CTX and other EGFR inhibitors results largely from activation of other signaling proteins (ErbB2, cMET, KRAS, BRAF or PI3K). We expect to show that the main reason for resistance to CTX is the insensitivity of EGFR to CTX along with ErbB2 overexpression; the impact of this paradigm- shifting concept on translational studies on EGFR-positive cancers should be significant. Findings from the project may also lay a solid foundation for clinical evaluation of hPEPDG278D against CRC and other cancers.

表皮生长因子受体（EGFR）是一种致癌受体酪氨酸激酶，是一种主要的治疗肿瘤的药物。 在几种类型的癌症中靶向。使用两种EGFR单克隆抗体（mAb）来治疗EGFR-1。 阳性结直肠癌（CRC），包括西妥昔单抗（CTX）和帕尼单抗，它们具有相同的 作用机制。不幸的是，对mAb的原发性和获得性耐药性非常常见： 仅10-20%的患者有反应，通常持续3-12个月。目前打击恐怖主义的办法 抗性是将mAb与靶向补偿性或改变的下游信号传导的药剂联合收割机组合 分子（ErbB 2、cMET、KRAS、BRAF和PIK 3CA），但这种方法的临床疗效不确定。 重要的是，我们发现hPEPDG 278 D，一种重组的人肽酶D的无酶活性突变体， 强烈抑制所有测试的CTX抗性CRC细胞系的增殖，并沉默EGFR、ErbB 2和 它们的下游信号分子。我们的研究结果表明EGFR和ErbB 2是关键的 CTX耐药CRC细胞中的治疗靶点。我们最近发现：a）hPEPDG 278 D特异性结合于 EGFR和ErbB 2的细胞外结构域，破坏它们的信号传导单位，并指导它们通过 内吞作用，因此是EGFR和ErbB 2的新型双重抑制剂; B）它选择性抑制癌细胞 在体外和体内过表达EGFR和/或ErbB 2; c）在小鼠研究中未显示毒性。的 我们的目标是进一步评估hPEPDG 278 D克服CTX耐药性的能力，并证实 EGFR和ErbB 2仍然是CTX耐药CRC细胞的关键治疗靶点的新概念。我们 假设hPEPDG 278 D通过抑制ErbB 2和CTX不敏感性来克服CTX抗性 EGFR，并提出了三个目的来检验假设。目的1是确定 hPEPDG 278 D在体内针对CTX抗性CRC肿瘤，使用直视肿瘤模型和患者模型。 衍生的异种移植模型。致癌性ErbB 3和ErbB 4（其他EGFR成员）以及cMET也是 与CRC中的CTX耐药性有关。目的2是研究hPEPDG 278 D是否间接抑制 使用两种细胞系，通过破坏它们与EGFR或ErbB 2的异二聚化， 并治疗来自Aim 1的肿瘤。除了靶向ErbB 2，hPEPDG 278 D还靶向CTX敏感性和 - 不敏感的EGFR。目的3是确定hPEPDG 278 D靶向CTX不敏感的细胞的机制。 （突变型或野生型）EGFR。总之，这是一个广泛接受的概念， CRC对CTX和其他EGFR抑制剂的耐药性主要来自其他信号传导的激活 蛋白质（ErbB 2、cMET、KRAS、BRAF或PI 3 K）。我们希望表明，抵抗的主要原因是 CTX是EGFR对CTX的不敏感性，沿着ErbB 2过表达;这种模式的影响- EGFR阳性癌症转化研究的概念转变应该是重要的。Findings from the 该项目也为hPEPDG 278 D抗CRC和其他癌症的临床评价奠定了坚实的基础。