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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