Growth Inhibition of Human Tumor Cells in Athymic Mice by Anti-Epidermal Growth Factor Receptor Monoclonal Antibodies

Traditionally, systemic treatment for high stage colorectal carcinoma (CRC) is mainly fluorouracil-based chemotherapy [1]. The anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, by acting on specific molecular pathways in tumor growth or modulating immune response towards tumor cells, provide a more targeted response, a better side effect profile and greater impact on patient survival compared with conventional molecules. This monoclonal antibody that binds the extracellular domain of epidermal growth factor receptor, is known to be effective only in a subset of KRAS wild-type colorectal cancers. Patients with mutations in either KRAS or NRAS gene are not eligible for anti-EGFR monoclonal antibody therapy [3]. This is due to downstream activation of the Ras/Raf/MAPK pathway by mutated RAS protein, leading to cell proliferation which cannot be sufficiently inhibited by anti-EGFR receptor monoclonal antibodies [4]. With the increasing choices of targeted agents, more and more biomarkers are tested. Currently, the standard recommended biomarker panel for colorectal carcinoma would include KRAS, NRAS, BRAF gene hotspot mutation detection and microsatellite instability test [5]. With the advances in genomic profiling and sequencing and the understanding of the resistance mechanisms, the contraindication of anti-EGFR therapy in mutant KRAS patients may be revised. Based on the fact that the KRAS mutation in CRC suppresses the phosphorylation of the AMP-activated protein kinase (AMPK) known to be toxic for the tumor cells, Hua et al obtained a satisfactory response to for the anti-EGFR antibodies in mutant KRAS CRC xenograft models after reactivation of the AMPK [6]. Knickelbein et al demonstrated that the anti-EGFR antibodies induce the death of CRC cells via a p73- dependent transcriptional activation of the pro-apoptotic Bcl-2 family protein (PUMA). This action is abolished in case of KRAS mutation. These authors admitted that the restoration of this pathway by inhibiting aurora kinases preferentially kills mutant KRAS CRC cells and overcomes KRAS-mediated resistance to anti-EGFR antibodies [7]. In fifty-one CRC patient-derived xenografts study, Lee et al showed that KRAS mutants expressed remarkably elevated autocrine levels of high-affinity EGFR ligands compared with wild-type KRAS. The use of an anti-EGFR IgG1 antibody that displays potent inhibitory effects on highaffinity EGFR ligand enhanced CRC KRAS mutant cells cytotoxicity [8]. Dealing with the resistance to targeted therapies in CRC patient looks feasible. It could allow to broaden the indications of anti-EGFR therapy and provide a better survival for a larger group of CRC patients. In this era of precision and personalized medicine, a complete case specific tumor profiling and the comprehensive study of the tumorogenesis mechanisms should allow to overcome the intrinsic and acquired resistance to these targeted high effective therapies.

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Association of SH2 Domain Protein Tyrosine Phosphatases with the Epidermal Growth Factor Receptor in Human Tumor Cells

Journal of Biological Chemistry ◽

10.1074/jbc.270.36.21277 ◽

1995 ◽

Vol 270 (36) ◽

pp. 21277-21284 ◽

Cited By ~ 111

Author(s):

Sinisa Tomic ◽

Udo Greiser ◽

Reiner Lammers ◽

Alexei Kharitonenkov ◽

Evgeny Imyanitov ◽

...

Keyword(s):

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Growth Factor Receptor ◽

Protein Tyrosine Phosphatases ◽

Human Tumor ◽

Sh2 Domain ◽

Human Tumor Cells ◽

Epidermal Growth ◽

Domain Protein

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To Give or Not to Give Anti–Epidermal Growth Factor Receptor (EGFR) Monoclonal Antibodies to Patients With KRAS G13D Mutation in Advanced Colorectal Cancer

Clinical Colorectal Cancer ◽

10.1016/j.clcc.2011.10.005 ◽

2012 ◽

Vol 11 (2) ◽

pp. 85-87 ◽

Cited By ~ 1

Author(s):

Richard Kim ◽

Timothy Kubal

Keyword(s):

Colorectal Cancer ◽

Epidermal Growth Factor Receptor ◽

Monoclonal Antibodies ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Advanced Colorectal Cancer ◽

Growth Factor Receptor ◽

Epidermal Growth

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The efficient production of monoclonal antibodies to the epidermal growth factor receptor

Journal of Immunological Methods ◽

10.1016/0022-1759(87)90257-2 ◽

1987 ◽

Vol 103 (1) ◽

pp. 153-154 ◽

Cited By ~ 1

Author(s):

Ivan King ◽

Alan C. Sartorelli

Keyword(s):

Epidermal Growth Factor Receptor ◽

Monoclonal Antibodies ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Growth Factor Receptor ◽

Efficient Production ◽

Epidermal Growth

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Clinicopathological variables of sporadic schwannomas of peripheral nerve in 291 patients and expression of biologically relevant markers

Journal of Neurosurgery ◽

10.3171/2017.2.jns153004 ◽

2018 ◽

Vol 129 (3) ◽

pp. 805-814 ◽

Cited By ~ 4

Author(s):

Eric D. Young ◽

Davis Ingram ◽

William Metcalf-Doetsch ◽

Dilshad Khan ◽

Ghadah Al Sannaa ◽

...

Keyword(s):

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Peripheral Nerve ◽

Tumor Cells ◽

Tissue Microarray ◽

Growth Factor Receptor ◽

Nerve Sheath ◽

Epidermal Growth

OBJECTIVEWhile sporadic peripheral schwannomas (SPSs) are generally well treated with surgery, their biology is not well understood. Consequently, treatment options are limited. The aim of this study was to provide a comprehensive description of SPS. The authors describe clinicopathological features and treatment outcomes of patients harboring these tumors, and they assess expression of biomarkers using a clinically annotated tissue microarray. Together, these data give new insight into the biology and management of SPS.METHODSPatients presenting with a primary SPS between 1993 and 2011 (n = 291) were selected from an institutional registry to construct a clinical database. All patients underwent follow-up, and short- and long-term outcomes were assessed. Expression of relevant biomarkers was assessed using a new tissue microarray (n = 121).RESULTSSPSs were generally large (mean 5.5 cm) and frequently painful at presentation (55%). Most patients were treated with surgery (80%), the majority of whom experienced complete resolution (52%) or improvement (18%) of their symptoms. Tumors that were completely resected (85%) did not recur. Some patients experienced short-term (16%) and long-term (4%) complications postoperatively. Schwannomas expressed higher levels of platelet-derived growth factor receptor–β (2.1) than malignant peripheral nerve sheath tumors (MPNSTs) (1.5, p = 0.004) and neurofibromas (1.33, p = 0.007). Expression of human epidermal growth factor receptor–2 was greater in SPSs (0.91) than in MPNSTs (0.33, p = 0.002) and neurofibromas (0.33, p = 0.026). Epidermal growth factor receptor was expressed in far fewer SPS cells (10%) than in MPNSTs (58%, p < 0.0001) or neurofibromas (37%, p = 0.007). SPSs more frequently expressed cytoplasmic survivin (66% of tumor cells) than normal nerve (46% of cells), but SPS expressed nuclear survivin in fewer tumor cells than in MPNSTs (24% and 50%, respectively; p = 0.018).CONCLUSIONSComplete resection is curative for SPS. Left untreated, however, these tumors can cause significant morbidity, and not all patients are candidates for resection. SPSs express a pattern of biomarkers consistent with the dysregulation of the tumor suppressor merlin observed in neurofibromatosis Type 2–associated schwannomas, suggesting a shared etiology. This SPS pattern is distinct from that of other tumors of the peripheral nerve sheath.

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