Novel Sensitizing Agents for Therapeutic Anti-EGFR Antibodies. Breaking Tolerance to Antibody-Mediated Immunotherapy Volume 1

Table of Contents

1. Introduction: Overview of anti-EGFR antibody therapy in cancer2. Molecular Mechanisms of Resistance to therapeutic antibodies to the Epidermal Growth Factor Receptor

Part I: 1?ERBB inhibitors as sensitizers for anti-EGFR antibodies3. MM-151 overcomes acquired resistance to cetuximab and panitumumab in colorectal cancers harboring EGFR extracellular domain mutations4. Sym004 Anti-EGFR Antibody Mixture overcomes resistance to anti-EGFR antibodies in Metastatic Colorectal Cancer5. HER3 Targeting with MM-121 Sensitizes HNSCC to Cetuximab by Reducing HER3 Activity and HER2/HER3 Dimerization6. Pan-HER, an Antibody Mixture Simultaneously Targeting EGFR, HER2, and HER3, Effectively Overcomes resistance to anti-EGFR antibodies.7. Pan-HER targeting with Four-in-one antibodies disrupting the HER/MET crosstalk8. Overcoming acquired resistance to cetuximab by combined EGFR and HER3 neutralizing monoclonal antibodies9. Dual targeting of EGFR and HER3 with MEHD7945A overcomes acquired resistance to EGFR inhibitors10. Inhibition of ERBB2 signaling overcome resistance to the EGFR-directed therapeutic antibody cetuximab11. Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR models

Part II: Alternative receptor tyrosine kinase inhibitors as sensitizers for anti-EGFR antibodies12. BET Inhibition Overcomes Receptor Tyrosine Kinase-Mediated Cetuximab Resistance in HNSCC13. Dual Inhibition of EGFR and c-Src by Cetuximab and Dasatinib Combined with FOLFOX Chemotherapy in Patients with Metastatic Colorectal Cancer14. A Novel Bispecific Antibody Targeting EGFR and cMet Is Effective against EGFR Inhibitor-Resistant Lung Tumors15. Use MET kinase inhibitor to overcome cetuximab resistance in CRC16. EGFR- and VEGF(R)-targeted small molecules show synergistic activity in colorectal cancer models refractory to combinations of monoclonal antibodies17. Antitumor activity of ZD6474, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, in human cancer cells with acquired resistance to anti epidermal growth factor receptor therapy

Part III: Downstream kinase inhibitors as sensitizers for anti-EGFR antibodies18. Antibody-mediated delivery of anti-KRAS-siRNA in vivo overcomes therapy resistance in colon cancer19. Primary and acquired resistance of colorectal cancer cells to anti-EGFR antibodies converge on MEK/ERK pathway activation and can be overcome by combined MEK/EGFR inhibition20. MEK1/2 inhibitors may be potential therapies for colorectal cancer that is resistant to EGFR monoclonal antibody therapy21. EGFR/JIP-4/JNK2 signaling attenuates cetuximab-mediated radiosensitization of squamous cell carcinoma cells22. Efficient blockade of Akt signaling is a determinant factor to overcome resistance to matuzumab.

Part IV: Other sensitizers for anti-EGFR antibodies23. Inhibition of SLC1A5 sensitizes colorectal cancer to cetuximab24. Targeting of PYK2 Synergizes with EGFR Antagonists in Basal-like TNBC and Circumvents HER3-Associated Resistance via the NEDD4-NDRG1 Axis25. Targeting EGFR/Notch to overcome resistance to anti-EGFR antibodies26. Hedgehog signaling alters reliance on EGF receptor signaling and mediates anti-EGFR therapeutic resistance in head and neck cancer27. Novel toll-like receptor 9 agonist induces epidermal growth factor receptor (EGFR) inhibition and synergistic antitumor activity with EGFR inhibitors28. Rationale for combination of therapeutic antibodies targeting tumor cells and immune checkpoint receptors

Authors

Shi Hu Lead, Research Laboratory, Department of Biophysics, Second Military Medical University, Shanghai, China. Dr. Shi Hu received an MD and a PhD in tumor immunology from Second Military Medical University, Shanghai, China. Since 2015, Dr. Hu leads a research laboratory in the Department of Biophysics, at second military medical university with a faculty position. His laboratory is interested in synthetic immunology based cancer therapeutics and antibody engineering, primarily development of novel sensitizers for antibody-based therapies (e.g., Anti-ERBB antibodies). Dr. Hu's research is currently supported by the National Natural Science Foundation of China.