Abstract:ERBB family members including epidermal growth factor receptor (EGFR) also known as HER1, ERBB2/HER2/Neu, ERBB3/HER3 and ERBB4/HER4 are aberrantly activated in multiple cancers and hence serve as drug targets and biomarkers in modern precision therapy. The therapeutic potential of HER3 has long been underappreciated, due to impaired kinase activity and relatively low expression in tumors. However, HER3 has received attention in recent years as it is a crucial heterodimeric partner for other EGFR family members… Show more
“…MM-111 is a bispecific antibody that simultaneously binds to Her3 and Her2 and results in an inhibition of the PI3K/pathway [85]. The safety and clinical effect of MM-111 combined with Trastuzumab are now being investigated in Her2 + and NRG + breast cancer in a different phase I/II clinical trial [86].…”
Section: Mm-111mentioning
confidence: 99%
“…As EGFRs are involved in cellular transformation, a number of small molecule inhibitors binding to the receptor tyrosine kinases have been developed (Table 1). Although mAbs achieve higher success rates in clinical trials when compared to tyrosine kinase inhibitors (TKIs) and also show a higher specificity as well as a lower toxicity, their production costs are higher and they can only inhibit extracellular targets, whereas the tyrosine kinase inhibitors can target both intra-and extracellular domains of EGFRs [86].…”
Section: Egfrs Small Molecule Inhibitors (Rtk Inhibitors)mentioning
The epidermal growth factor receptor (EGFR) family contains four transmembrane tyrosine kinases (EGFR1/ErbB1, Her2/ErbB2, Her3/ErbB3 and Her4/ErbB4) and 13 secreted polypeptide ligands. EGFRs are overexpressed in many solid tumors, including breast, pancreas, head-and-neck, prostate, ovarian, renal, colon, and non-small-cell lung cancer. Such overexpression produces strong stimulation of downstream signaling pathways, which induce cell growth, cell differentiation, cell cycle progression, angiogenesis, cell motility and blocking of apoptosis.The high expression and/or functional activation of EGFRs correlates with the pathogenesis and progression of several cancers, which make them attractive targets for both diagnosis and therapy. Several approaches have been developed to target these receptors and/or the EGFR modulated effects in cancer cells. Most approaches include the development of anti-EGFRs antibodies and/or small-molecule EGFR inhibitors. This review presents the state-of-the-art and future prospects of targeting EGFRs to treat breast cancer.
“…MM-111 is a bispecific antibody that simultaneously binds to Her3 and Her2 and results in an inhibition of the PI3K/pathway [85]. The safety and clinical effect of MM-111 combined with Trastuzumab are now being investigated in Her2 + and NRG + breast cancer in a different phase I/II clinical trial [86].…”
Section: Mm-111mentioning
confidence: 99%
“…As EGFRs are involved in cellular transformation, a number of small molecule inhibitors binding to the receptor tyrosine kinases have been developed (Table 1). Although mAbs achieve higher success rates in clinical trials when compared to tyrosine kinase inhibitors (TKIs) and also show a higher specificity as well as a lower toxicity, their production costs are higher and they can only inhibit extracellular targets, whereas the tyrosine kinase inhibitors can target both intra-and extracellular domains of EGFRs [86].…”
Section: Egfrs Small Molecule Inhibitors (Rtk Inhibitors)mentioning
The epidermal growth factor receptor (EGFR) family contains four transmembrane tyrosine kinases (EGFR1/ErbB1, Her2/ErbB2, Her3/ErbB3 and Her4/ErbB4) and 13 secreted polypeptide ligands. EGFRs are overexpressed in many solid tumors, including breast, pancreas, head-and-neck, prostate, ovarian, renal, colon, and non-small-cell lung cancer. Such overexpression produces strong stimulation of downstream signaling pathways, which induce cell growth, cell differentiation, cell cycle progression, angiogenesis, cell motility and blocking of apoptosis.The high expression and/or functional activation of EGFRs correlates with the pathogenesis and progression of several cancers, which make them attractive targets for both diagnosis and therapy. Several approaches have been developed to target these receptors and/or the EGFR modulated effects in cancer cells. Most approaches include the development of anti-EGFRs antibodies and/or small-molecule EGFR inhibitors. This review presents the state-of-the-art and future prospects of targeting EGFRs to treat breast cancer.
“…2020, 21, 1972 2 of 16 activates the potent PI3K/AKT/mTor signaling pathway, affecting cell proliferation and survival [1], and upregulation of HER3 can be a bypass mechanism for signaling loss of other HER-family members due to HER-targeted therapy [4,5]. Co-expression of HER3 is, therefore, considered a cause for the development of therapy resistance, which has, for instance, been documented for the tyrosine kinase inhibitors (TKIs) lapatinib and gefitinib, targeting epidermal growth factor receptor (EGFR) and HER2 [6][7][8]. Thus, inhibition of HER3-mediated signaling might have potential to overcome therapy resistance [4,9] and monitoring of HER3 expression could, therefore, aid strategic decision making for cancer therapy.…”
HER3-binding affibody molecules are a promising format for visualization of HER3 expression. Cobalt-55, a positron-emitting isotope, with a half-life of 17.5 h, allows for next-day imaging. We investigated the influence of the charge of the radiocobalt–chelator complex on the biodistribution of anti-HER3 affibody molecule (HE)3-ZHER3 and compared the best radiocobalt-labeled variant with a recently optimized gallium-labeled variant. Affibody conjugates (HE)3-ZHER3-X (X = NOTA, NODAGA, DOTA, DOTAGA) were labeled with [57Co]Co (surrogate for 55Co). Affinity measurements, binding specificity and cellular processing were studied in two HER3-expressing cancer cell lines. Biodistribution was studied 3 and 24 h post-injection (pi) in mice with HER3-expressing BxPC-3 xenografts and compared to [68Ga]Ga-(HE)3-ZHER3-NODAGA. Micro-single-photon emission tomography/computed tomography (microSPECT/CT) and micro-positron emission tomography/computed tomography (microPET/CT) imaging was performed 3 and 24 h pi. Stably labeled conjugates bound to HER3 with subnanomolar affinity. [57Co]Co-(HE)3-ZHER3-DOTA had the best tumor retention and a significantly lower concentration in blood than other conjugates, leading to superior tumor-to-blood and tumor-to-liver ratios 24 h pi. Compared to [68Ga]Ga-(HE)3-ZHER3-NODAGA 3 h pi, [57Co]Co-(HE)3-ZHER3-DOTA provided superior imaging contrast in liver 24 h pi. Concluding, the composition and charge of the [57Co]Co–chelator complex influenced the uptake in tumors and normal tissue. [57Co]Co-(HE)3-ZHER3-DOTA provided the best imaging properties among the cobalt-labeled conjugates. Delayed imaging of HER3 expression with [57Co]Co-(HE)3-ZHER3-DOTA improved imaging contrast compared to early-time-point imaging with [68Ga]Ga-(HE)3-ZHER3-NODAGA.
“…CDDP treatment significantly upregulated phosphatase Ppp2r2a (also known as B55A), death-associated protein kinase Dapk1 as well as Mapk1/2 kinases that are stimulated upon extra-and intracellular signals. Exclusive to CsA is the down-regulation of various signaling pathways (Granzyme B, ErbB2, NGF, Rho GTPase, AML) that are among others involved in the regulation of cell cycle, apoptosis and extracellular matrix degradation (Mishra et al 2018). Moreover, these pathways are known to be linked to kinases (i.e.…”
Damage to cellular macromolecules and organelles by chemical exposure evokes activation of various stress response pathways. To what extent different chemical stressors activate common and stressor-specific pathways is largely unknown. Here, we used quantitative phosphoproteomics to compare the signaling events induced by four stressors with different modes of action: the DNA damaging agent: cisplatin (CDDP), the topoisomerase II inhibitor: etoposide (ETO), the prooxidant: diethyl maleate (DEM) and the immunosuppressant: cyclosporine A (CsA) administered at an equitoxic dose to mouse embryonic stem cells. We observed major differences between the stressors in the number and identity of responsive phosphosites and the amplitude of phosphorylation. Kinase motif and pathway analyses indicated that the DNA damage response (DDR) activation by CDDP occurs predominantly through the replication-stress-related Atr kinase, whereas ETO triggers the DDR through Atr as well as the DNA double-strand-break-associated Atm kinase. CsA shares with ETO activation of CK2 kinase. Congruent with their known modes of action, CsA-mediated signaling is related to down-regulation of pathways that control hematopoietic differentiation and immunity, whereas oxidative stress is the most prominent initiator of DEM-modulated stress signaling. This study shows that even at equitoxic doses, different stressors induce distinctive and complex phosphorylation signaling cascades.
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