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Combating Cetuximab Resistance in Colorectal Cancer

对抗结直肠癌中的西妥昔单抗耐药性

基本信息

批准号：
10115631
负责人：
YUESHENG ZHANG
金额：
$ 4.34万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
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/10115631
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 base cancer cell cancer type clinical efficacy colon cancer cell line colorectal cancer treatment gain of function mutation hypoxia inducible factor 1 in vivo knock-down member mutant novel overexpression panitumumab patient derived xenograft model receptor binding research clinical testing response targeted agent therapeutic target therapeutically effective tool translational study tumor

项目摘要

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，是一种主要的治疗方法