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Squamous Cell Carcinoma
Published in Debjani Sahni, Adam Lerner, Bilal Fawaz, Advanced Skin Cancer, 2022
Systemic therapies are used mostly for metastatic cSCCs but are also considered for unresectable disease or when RT is not possible. In recent years, two classes of therapies have emerged for cSCC treatment: Targeted and immunologic therapies. The main targeted therapy is in the form of EGFR inhibitors (e.g., cetuximab). EGFR is expressed in more than 90% of cSCC and is responsible for cellular proliferation, survival, angiogenesis, and metastasis. In 2006, the FDA approved cetuximab for the treatment of locally advanced or metastatic mucosal SCC. Its use in cSCC is still off-label. The other form of systemic treatment currently approved for use in cSCC is checkpoint inhibitor immunotherapy, specifically the PD-1 inhibitor cemiplimab.12
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Finally, it is worth noting that skin rashes are the most common adverse reactions associated with EGFR inhibitors, and many clinicians believe that this may be a useful biomarker of drug activity. However, sometimes this effect can be very harmful to patients, and cases of keratitis and ulcerative keratitis have been reported following treatment with EGFR inhibitors including erlotinib, gefitinib cetuximab, and panitumumab. In rare cases, this has resulted in corneal perforation and blindness.
Gastrointestinal cancer
Published in Peter Hoskin, Peter Ostler, Clinical Oncology, 2020
First-line chemotherapy is based on a two-drug combination, usually 5FU with folinic acid and oxaliplatin (FOLFOX) or irinotecan (FOLFIRI). Capecitabine may be used in place of 5FU/folinic acid. In addition, biological agents have been shown to enhance the response to chemotherapy using either a VEGF inhibitor (bevacizumab or regorafenib) or EGFR inhibitor (cetuximab or panitumumab). The EGFR inhibitor combinations are indicated in patients with NRAS or KRAS wild-type mutations.
Triple targeting of mutant EGFRL858R/T790M, COX-2, and 15-LOX: design and synthesis of novel quinazolinone tethered phenyl urea derivatives for anti-inflammatory and anticancer evaluation
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Hend Kothayer, Samar Rezq, Ahmed S. Abdelkhalek, Damian G. Romero, Samar S. Elbaramawi
Epidermal growth factor receptor (EGFR) is a protein kinase that is overexpressed in a variety of human solid tumours, including pancreatic, colorectal, non-small cell lung (NSCLC), renal cell carcinoma (RCC), ovarian, breast, and head and neck cancers2,5. Thus EGFR inhibitors have become widely used for the treatment of those cancers. Although many tumours show an initial response to the treatment with EGFR inhibitors, resistance to treatment often occurs due to point mutations in the ATP binding pocket of EGFR, such as T790M, L858R, and C797S. These mutations have resulted in the development of three generations of EGFR tyrosine kinase inhibitors (TKIs)2,6. EGFR classic mutations are in-frame deletions in exon 19 and an L858R point mutation in exon 21. First-generation EGFR inhibitors (4- amino quinazolines) erlotinib (A) and gefitinib (B) were efficacious for these classic mutations (Figure 1). However, resistance develops after the administration of first-generation EGFR TKIs due to a secondary mutation where a bulkier methionine replaces threonine at position 790 (gate keeper) (T790M). The bulkier methionine group sterically hinders the binding of these reversible inhibitors. Also, the T790M mutation confers an increased affinity for ATP to bind with the receptor6–10.
Targeting the EGFR signaling pathway in cancer therapy: What’s new in 2023?
Published in Expert Opinion on Therapeutic Targets, 2023
Sushanta Halder, Soumi Basu, Shobhit P. Lall, Apar K. Ganti, Surinder K. Batra, Parthasarathy Seshacharyulu
Numerous studies have shown that EGF stimulation led to the activation of EGFR downstream signaling driving the cellular phenotype of epithelial cells. Treatment of non-epithelial and cancerous epithelial cells using EGFR inhibitors demonstrated an inhibited network of EGFR signaling events. EGFR family members’ overexpression was associated with poor clinical outcomes in all cancers. EGFR gene expression and protein expression in various cancers are summarized in Figure 4 and Table 2. Over several years of research, our research community has identified several targeted therapies against activated and mutated EGFR, HER2, HER3, and HER4 (panEGFR inhibitors). These agents were approved by the US FDA, the European Medicines Agency (EMA), and the National Medical Products Administration (NMPA) in China for early, late, and advanced-stage cancer patients. More importantly, EGFR-targeted inhibitors are the first molecular agents to be approved and applied for several advanced cancers. They are the first targeted agents to be used as monotherapy with superior efficacy over conventional chemotherapy in cancer patients.
RNA-Seq Analysis of Clinical Samples from TCGA Reveal Molecular Signatures for Ovarian Cancer
Published in Cancer Investigation, 2023
Rucha M. Wadapurkar, Aruna Sivaram, Renu Vyas
Association of the expression levels with disease progression was observed in two genes – the EGF and CXCL8, where the expression was found to be decreasing as the disease progresses. Most of the other genes were found to have a consistent expression across different stages. Role of EGF and CXCL8 in cancers have been well documented. EGF and CXCL8 play important roles in angiogenesis during tumor progression. EGFR inhibitor is one of the common therapies for diseases like lung cancer and pancreatic cancer. However, inhibition of EGFR exhibits only modest effect on ovarian cancer patients. It is imperative to understand if lower levels of EGF in advanced stages, as predicted in this study, is contributing towards the low efficacy of EGFR inhibitors. For further understanding, it is essential to evaluate all the tumorogenic events controlled by EGF/EGFR axis. Studies have shown that knockdown of IL-8 sensitised the cells towards platinum based drugs (38). A better insight into the angiogenesis process and the role of immune cells in tumor progression will help us in understanding the trends observed in the current study. One of the major limitations of the study is that it relies mainly on the in siliso data. The data requires further validation in in vitro and in vivo models as well as in clinical samples in order to establish these genes as diagnostic biomarker for the disease in different category of patients. Nevertheless, this study brings us one step closer to the identification of potential diagnostic biomarkers for the disease.