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: 9453661
• 负责人: YUESHENG ZHANG
• 金额: $ 40.06万
• 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/9453661
• 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; X-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，是一种主要的治疗性 靶向几种类型的癌症。两种EGFR单克隆抗体（mAb）用于治疗EGFR- 阳性结直肠癌（CRC），包括西妥昔单抗（CTX）和Panitumumab，它们具有相同的 作用机理。不幸的是，对mAb的主要和获得的抗性非常普遍： 仅10％至20％的患者反应，通常持续3-12个月。当前打击的方法 电阻是将mAb与靶向代偿性或变化下游信号的试剂相结合 分子（ERBB2，CMET，KRAS，BRAF和PIK3CA），但是这种方法的临床功效尚不确定。 重要的是，我们发现HPEPDG278D是人肽酶D的重组非活性突变体， 强烈抑制所有测试过CTX的CRC细胞系的增殖，并使EGFR，ERBB2和 它们在这些细胞中的下游信号分子。我们的结果表明EGFR和ERBB2是关键的 耐CTX的CRC细胞中的治疗靶标。我们最近显示：a）HPEPDG278D专门结合了 EGFR和ERBB2的细胞外域，破坏了它们的信号单位，并通过 内吞作用，因此是EGFR和ERBB2的新型双重抑制剂。 b）它有选择地抑制癌细胞 在体外和体内过表达EGFR和/或ERBB2； c）它在小鼠研究中没有显示毒性。这 我们建议的目标是进一步评估HPEPDG278D，以克服CTX抵抗力并证实 EGFR和ERBB2在CTX耐CRC细胞中仍然是关键的治疗靶标的新颖概念。我们 假设HPEPDG278D通过抑制ERBB2和CTX不敏感来克服CTX的抗性 EGFR，并提出三个旨在检验假设的旨在。目的1是确定的治疗功效 使用正常肿瘤模型和患者 - 派生的异种移植模型。致癌ERBB3和ERBB4（其他EGFR成员）以及CMET也是 与CRC中的CTX抗性有关。 AIM 2是研究HPEPDG278D是否间接抑制 使用两种细胞系，ERBB3，ERBB4和CMET通过使用EGFR或ERBB2的异二聚化来破坏它们的异二聚化 并从AIM 1进行处理的肿瘤。除了靶向ERBB2外，HPEPDG278D还针对CTX敏感和 - 不敏感的EGFR。 AIM 3是确定HPEPDG278D靶向CTX不敏感的机制 （突变或野生型）EGFR在相关的CRC细胞系中。总而言之，这是一个广泛接受的概念 CRC对CTX和其他EGFR抑制剂的抗性主要是由于其他信号的激活而导致的 蛋白质（ERBB2，CMET，KRAS，BRAF或PI3K）。我们希望表明抵抗的主要原因 CTX是EGFR对CTX的不敏感性，以及ERBB2的过表达。这个范式的影响 关于EGFR阳性癌症的翻译研究的转移概念应该很重要。来自 项目还可能为针对CRC和其他癌症的HPEPDG278D临床评估奠定坚实的基础。