title: Broad RTK-targeted therapy overcomes molecular heterogeneity-driven resistance to cetuximab via vectored immunoprophylaxis in colorectal cancer.
abstract: The human epidermal growth factor receptor (EGFR) targeting chimeric monoclonal antibody, cetuximab (Erbitux®), is a widely used drug in the treatment of metastatic colorectal cancer. However, the activation of the extensive crosstalk among the EGFR family receptors as well as other tyrosine kinase receptors (RTKs) impairs the efficacy of the drug by fueling acquired resistance. To identify the responsible potential activation pathway underlying cetuximab resistance and generate novel treatment strategies, cetuximab-resistant colorectal cancer cell lines were generated and validated and a functional RNAi screen targeting human RTKs was used to identify extensive receptor tyrosine kinase signaling networks established in resistant cancer cells. MET, Axl, and IGF-1R were identified as contributors to the acquired resistance to cetuximab. Targeting vectored immunoprophylaxis (VIPs) to different RTKs were generated and characterized. Different VIP approaches were evaluated in vivo with parental and cetuximab-resistance xenografts and the RTKs in resistant cancer xenografts were inhibited with VIPs via re-sensitization to cetuximab treatment. Combination of VIPs was more broadly efficacious, mechanistically, due to co-blocking the EGFR/Axl/MET signaling pathway, which was cross-activated in the resistant cell lines. Moreover, a VIP-based procedural treatment strategy not only eliminated the tumor but also afforded long-lasting protection from tumor recurrence and resistance. Overall, EGFR-related RTK pathway-network activation represents a novel mechanism underlying cetuximab resistance. A broad VIP combination strategy and VIP-based procedural treatment strategy may be a recommended addition to cetuximab-based targeted therapy. Our results establish a new principle to achieve combined RTK inhibition and reverse drug resistance using a VIP approach.
authors: Department of Biophysics, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China. Electronic address: hus@smmu.edu.cn.
authors: Shi
authors: S
authors: Hu
authors: Department of Anesthesiology, School of Medicine, Jinling Hospital, Nanjing University, Nanjing 210002, China.
authors: Haibin
authors: H
authors: Dai
authors: Department of Biophysics, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China.
authors: Tian
authors: T
authors: Li
authors: Department of Biophysics, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China.
authors: Ying
authors: Y
authors: Tang
authors: Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors: Wenyan
authors: W
authors: Fu
authors: Department of Biophysics, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China.
authors: Qingning
authors: Q
authors: Yuan
authors: Department of Biophysics, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China.
authors: Feifei
authors: F
authors: Wang
authors: Department of Biophysics, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China.
authors: Gaojian
authors: G
authors: Lv
authors: Department of Biophysics, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China.
authors: Yuanyuan
authors: Y
authors: Lv
authors: Department of Biophysics, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China.
authors: Xiaoyan
authors: X
authors: Fan
authors: Department of Emergency Medicine, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
authors: Sheng
authors: S
authors: Zhang
authors: Department of Nephrology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
authors: Ruobing
authors: R
authors: Jin
authors: Department of Biophysics, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China.
authors: Yafeng
authors: Y
authors: Shen
authors: Department of Biophysics, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China.
authors: Fangxing
authors: F
authors: Lin
authors: Department of Biophysics, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China.
authors: Xuting
authors: X
authors: Ye
authors: Molecular Drug Discovery Center, Fengchao Medical Technology (Shanghai) Co. Ltd., Shanghai, 200235, China.
authors: Min
authors: M
authors: Ding
authors: Department of Biophysics, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China.
authors: Yongji
authors: Y
authors: Yang
authors: Department of Biophysics, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China. Electronic address: lei@smmu.edu.cn.
authors: Changhai
authors: C
authors: Lei
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D000229:Dependovirus / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D034622:RNA Interference; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; C569480:dalotuzumab; C583360:ficlatuzumab; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases; D000068818:Cetuximab; D000094963:Axl Receptor Tyrosine Kinase
keywords: Acquire resistance; Broad targeted therapy; CRC; Viral vectors