Novel Sensitizing Agents for Therapeutic Anti-EGFR Antibodies

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Novel Sensitizing Agents for Therapeutic Anti-EGFR Antibodies
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Aims and Scope of Series ``Breaking Tolerance to Antibody-Mediated Immunotherapy´´
About the Series Editor
Aims and Scope of Volume
About the Volume Editor
Preface
Contents
Contributors
Chapter 1: Current status of anti-EGFR agents
	Introduction
	Targeting EGFR
	Novel EGFR targeting strategies
	Conclusions
	References
Chapter 2: Molecular mechanisms of resistance to the EGFR monoclonal antibody cetuximab
	Introduction
	EGFR biology
	The role of EGFR in human cancer
	The function of EGFR-targeted antibodies
	Cetuximab in the clinic
	Mechanisms of resistance to EGFR-targeted antibodies
	EGFR mutations
	EGFR gene copy number as a predictor of response
	EGFR ligand state
	KRAS mutations as a predictor of response
	BRAF mutation as a predictor of response
	Mechanisms of resistance against EGFR-targeted antibodies
		Angiogenesis
	Disorders of EGFR internalization and degradation
	Oncogenic shift
	Subcellular localization of EGFR
	Epithelial cells transform into mesenchymal cells
	Constitutive activation of EGFR downstream effector molecules
	Increased expression of HER family growth factors
	Concluding remarks
	References
Chapter 3: MM-151 overcomes acquired resistance to cetuximab and panitumumab in colorectal cancers harboring EGFR extrace
	Introduction
	EGFR ECD mutations do not affect ligand-receptor binding but do affect antibody-receptor binding
	MM-151 can inhibit the growth of LIM1215 cells overexpressing EGFR ECD mutants
	MM-151 can inhibit the growth of cetuximab-resistant clones in spontaneous models
	MM-151 reduced the frequency of EGFR-ECD allele mutations
	Discussion
	References
	Further reading
Chapter 4: Sym004 anti-EGFR antibody mixture overcomes resistance to anti-EGFR antibodies in metastatic colorectal cancer
	EGFR and CRC
	SYM004 compared with cetuximab
	Cell proliferation and induction of apoptosis
	EGFR-dependent intracellular signaling/MET activation and ERBB2 amplification
	Tumor xenograft models of human colorectal cancer
		HER2
		Final thoughts and future directions
	References
Chapter 5: Broad RTK-targeted therapy overcomes molecular heterogeneity-driven resistance to cetuximab via vectored immun ...
	Study on the related functional signaling network pathway based on the drug resistance of targeted monoclonal antibodies in CRC
	Phased therapeutic strategy of antibody transformation in vivo based on VIP background
	In vivo experiments were conducted to characterize the relationship between pathway crosstalk of key gene effectors and dru ...
	Cross design and effect presentation of VIP therapeutic drugs and carriers
	Final summary and assumption
	References
Chapter 6: Pan-HER, an antibody mixture, simultaneously targeting EGFR, HER2, and HER3 effectively overcomes resistance
	References
Chapter 7: Four-in-one antibodies have superior cancer inhibitory activity against EGFR, HER2, HER3, and VEGF through dis ...
	Introduction
	Design and characterization of four-in-one antibodies
	Four-in-one antibodies can effectively inhibit EGFR, HER2, HER3, and VEGFR2
	The four-in-one antibody has excellent antitumor activity both in vitro and in vivo
	Only four-in-one antibodies interfere with HER/MET crosstalk
	MET/HER signaling is critical for resistance to HER-targeted therapy
	Four-in-one antibodies can overcome resistance to HER therapy
	Discussion
	References
Chapter 8: Overcoming acquired resistance to cetuximab by combining EGFR- and HER3-neutralizing monoclonal antibodies
	EGFR inhibitor tolerance is related to both EGFR and HER3, which MEHD7945A completely targets
	MEHD7945A inhibits the growth of two tumor cell lines that are resistant to cetuximab
	MEHD7945A inhibits the growth of human tumor xenografts that are resistant to EGFR inhibitors
	MEHD7945A inhibits radiation-induced survival and overcomes cross-resistance to radiation
	mAb33: A neutralizing anti-HER3 antibody that prevents resistance to an EGF kinase inhibitor
	Combining osimertinib with mAb33 overcomes resistance by upregulating HER3 and inhibiting the release of the soluble extrac ...
	Combination of mAb33, cetuximab, and osimertinib inhibits growth of human tumor xenografts by simultaneously inhibiting oth ...
	The drug combination comprising mAb33 delays relapse of a model derived from a patients metastatic lesion
	Discussion
	References
Chapter 9: Dual targeting of EGFR and HER3 with MEHD7945A overcomes acquired resistance to EGFR inhibitors and radiat
	HER3 is an essential regulatory target for acquired drug resistance
	The mechanism of MEHD7945A in overcoming acquired drug resistance through tumor xenografts and cells
	Study on the mechanism of MEHD7945A in radiation-damaged cells
	Final thoughts and future directions
	References
Chapter 10: Targeting ERBB2 overcomes resistance to the anti-EGFR therapeutic antibody cetuximab
	Introduction
	ERBB2 amplification mediates cetuximab resistance through Erk1/2 signaling
	Heregulin activates ERBB2 signaling and mediates resistance to cetuximab without ERBB2 amplification
	611-CTF, a C-terminal fragment of HER2, is phosphorylated in cetuximab-resistant cells
	Targeting ERBB2 signaling overcomes resistance to cetuximab: Preclinical studies
	Dual inhibition of ERBB2 and EGFR in cetuximab-resistant patients: Clinical trials
	Conclusion
	References
Chapter 11: CT16: A dual antibody targeting both EGFR and Notch suppresses EGFR blockage and radiation resistance by decrea
	Introduction
	Combined use of EGFR inhibitors and irradiation can promote EMT and stem cell-like properties in NSCLC cells
	Enrichment of the ALDH+ cell population depends on Notch2/3 receptors
	Dual blockade of EGFR and Notch2/3 inhibits resistance to EGFR inhibitors in vitro
	Dual blockade of EGFR and Notch2/3 inhibits resistance to EGFR inhibitors in vivo
	CT16 enhances the radiosensitivity of cancer cells and reduces the ALDH+ cell populations
	CT16 can reduce the proliferation of tumor cells and shows good antitumor activity
	Dual blockade of EGFR and Notch2/3 reduces the number of CSCs and delays tumor recurrence after radiotherapy
	Discussion
	References
Chapter 12: BET inhibition overcomes receptor tyrosine kinase-mediated cetuximab resistance in HNSCC
	Introduction
	The HNSCC model of acquired cetuximab resistance relies on surrogate RTK activity
	Pharmacological inhibition of BET family members overcame cetuximab resistance in vitro
	Blocking BET can inhibit the expression of RTK in the HNSCC model of cetuximab
	RTK overexpression mediates resistance to cetuximab and BET inhibition
	BET blocking prevents the acquisition of cetuximab resistance in the PDX model of HNSCC patients
	Expression of RTK and BRD4 genes in a clinical cohort of HNSCC
	Conclusion
	References
Chapter 13: Dual inhibition of EGFR and c-Src by cetuximab and dasatinib combined with FOLFOX chemotherapy in patien
	Combination synergistic chemotherapy of mCRC treatment
	Phase IB: Safety and efficacy
	Phase II: The role of KRAS mutation
	RAS amplification and KRAS mutation
	IBD and KRAS-amplified mCRC
	Discussion and future directions
	References
Chapter 14: A novel bispecific antibody targeting EGFR and cMet is effective against EGFR inhibitor-resistant lung tumors
	References
Chapter 15: Use of MET kinase inhibitors to overcome cetuximab resistance in colorectal cancer
	Introduction
	EGFR and MET are coexpressed in a genotypically diverse panel of cetuximab-sensitive CRC cell lines
	Combined activation of EGFR and MET enhances CRC cell proliferation by augmenting the activation of AKT and MAPK
	HGF induces resistance to cetuximab through MET activation
	HGF rescues CRC cells from cetuximab-induced G1 arrest
	HGF rescued the apoptosis of DiFi cells induced by cetuximab
	HGF rescue occurs via MET-dependent activation of AKT and MAPK
	Discussion
	References
Chapter 16: EGFR- and VEGF(R)-targeted small molecules show synergistic activity in colorectal cancer models refractory t ...
	An important oncogenic signaling pathway: Intracellular signal transduction
	Mechanistic differences and activity comparison between TKIs and mAbs
	Final thoughts and future directions
	References
Chapter 17: Antitumor activity of the VEGFR inhibitor ZD6474 in human cancer cells resistant to anti-EGFR therapy
	Introduction
	ZD6474 efficiently inhibited the growth of EGFR-resistant tumors via inhibition of VEGFR
	The combination of ZD6474 and cetuximab displayed a synergistic antitumor effect against multiple cancer cell lines
	Discussion
	References
Chapter 18: Antibody-mediated delivery of anti-KRAS-siRNA overcomes therapy resistance in colon cancer
	Introduction
	Generation and characterization of KRAS-siRNA-anti-EGFR antibody complexes
	In vitro validation of KRAS-siRNA-anti-EGFR antibody complexes: KRAS silencing and tumor inhibitory activity
	In vivo antitumor effect of the cetuximab-KRAS-esiRNA complex
	Final thoughts and future directions
	References
Chapter 19: Primary and acquired resistance of colorectal cancer cells to anti-EGFR antibodies converge on MEK/ERK pathwa
	References
Chapter 20: MEK1/2 inhibitors AS703026 and AZD6244 may be potential therapies for KRAS-mutated colorectal cancer that is  ...
	The status of K-RAS mutations is the key influencing factor in determining cetuximab resistance sensitivity
	Efficacy in the ERK pathway, proliferation, transformation, and tumor growth in cetuximab-resistant tumor cells caused by K ...
	The development of MEK inhibitors and the discovery of their mechanism of action
	Final thoughts and future directions
	References
Chapter 21: EGFR/JIP-4/JNK2 signaling attenuates cetuximab-mediated radiosensitization of squamous cell carcinoma cells
	3-Dimensional (3D) extracellular matrix (ECM) for studying how HNSCC cells grow in vivo
	Growth conditions play an important role in EGFR phosphorylation and signaling
	Cytotoxicity and radiosensitizing potential of cetuximab
	Phosphoproteome modifications after cetuximab-mediated EGFR inhibition
	JNK2 depletion enhances cetuximab-induced radiosensitization
	JIP-4 connects EGFR to JNK2
	Discussion
	References
Chapter 22: EGFR/Notch antagonists enhance the response to inhibitors of the PI3K-Akt pathway by decreasing t
	References
Chapter 23: Inhibition of SLC1A5 sensitizes colorectal cancer to cetuximab
	Introduction
	SLC1A5 is overexpressed in cancer tissues of cetuximab-resistant CRC patients
	SLC1A5 promotes the proliferation of CRC both in vitro and in vivo
	Targeting SLC1A5 significantly enhanced the inhibitory effect of cetuximab on CRC proliferation
	Targeting SLC1A5 increases ubiquitin-proteasome pathway-mediated EGFR degradation
	Inhibition of SLC1A5 induces DNA damage in CRC cells
	Discussion
	References
	Further reading
Chapter 24: Targeting of PYK2 synergizes with EGFR antagonists in basal-like TNBC and circumvents HER3-associated resis
	References
Chapter 25: Overcoming acquired resistance to EGFR-targeted therapy by regulating autophagy
	Overlap between EGFR and autophagy regulatory signaling
	Autophagy facilitates tumor resistance to targeted biological therapies
	Targeting autophagy helps solve the problem of resistance to anti-EGFR treatments
	miRNAs and EVs regulate both autophagy and the response of cancer cells to anti-EGFR treatments
	Antiautophagic peptides that modulate the effect of anti-EGFR therapy on tumor cells
	Discussion
	References
Chapter 26: Hedgehog signaling alters reliance on EGF receptor signaling and mediates anti-EGFR therapeutic resistance in ...
	Introduction
	Crosstalk between EGFR and HhP in HNSCC
	Combination of cetuximab and IPI-926 in preclinical models
	Conclusion
	References
Chapter 27: Novel Toll-like receptor 9 agonist induces epidermal growth factor receptor (EGFR) inhibition and synergistic ...
	The ability of CpG DNA to affect tumor growth related to EGFR pathways
	IMO combined with cetuximab inhibits the expression and angiogenesis of signaling proteins and causes potent antitumor activity
	The in vitro effect of IMO is not obvious
	Cooperation of IMO and the EGFR tyrosine kinase inhibitor gefitinib has a combined effect
	IMO has no inhibitory effect on the growth of cetuximab-resistant GEO-CR xenografts but still cooperates with cetuximab
	Tumor xenografts can achieve eradication under administration of IMO in combination with cetuximab and irinotecan
	Discussion
	References
Chapter 28: Targeted cancer therapy: The future of drug combinations
	Introduction
	Molecular bases of cancer and growth factor pathway
	Cancer therapy and mechanisms underlying drug action/resistance
	Therapeutic mAbs: Mechanisms of action and combinations
	Future expectations regarding the PD-1/PD-L1 pathways
	A different way of classifying tumor resistance
	Does endocytosis/EGFR downregulation explain resistance to mAbs?
	Conclusion and future tendencies
	References
Index
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