Small Molecules with EGFR-TK Inhibitor Activity

Abstract

Specific and reversible EGFR tyrosine kinase inhibitors (TKI) such as gefitinib and erlotinib are clinically active in advanced or metastatic NSCLC and both are approved in various countries for the treatment of patients that failed prior chemotherapy. Erlotinib has also prolonged survival in pancreatic cancer patients when added to gemcitabine and regulatory approval in this disease is being sought. Additional promising activity has been seen in other tumor types, such as ovarian cancer or head and neck malignancies, and phase III trials in these malignancies are ongoing or planned. Despite these successes, these agents have exhibited anecdotal or modest activity when used as single agents in unselected patients with various other tumor types. We have learned that the clinical development of these agents is far from simple and we need to better understand biological and clinical criteria for patient selection and how to best use the different available agents. The recent discovery of EGFR mutations and the potential identification of other markers that might predict patient response could help to optimize the use of these agents in the future. Irreversible EGFR inhibitors, dual EGF/HER2 and pan-ErbB receptor inhibitors may have greater antitumor activity although the tolerance of these compounds compared to specific EGFR TKIs needs further characterization. HER2 specific TKIs are also in development. Lapatinib, a dual EGFR/HER2 TK inhibitors, is particularly promising in breast cancer. Newer agents, such as BMS-599626, have recently entered into the clinic. In addition to the use of these agents as single agents, many clinical studies are addressing the role of combining them with hormonal agents, biological agents or chemotherapy.

A phase II and pharmacodynamic study of gefitinib in patients with refractory or recurrent epithelial ovarian cancer

“…16 Prior preclinical and clinical studies have shown decreased EGFR and diminished activation in unproven surrogates. 19,32 To our knowledge, this is one of the first studies to provide tumor-specific evidence of tyrosine kinase inhibition by gefitinib in a clinical setting. We also demonstrated that inhibition of p-EGFR results in the inhibition of downstream signaling molecules known to transmit the EGFR growth response.…”

“…17 Gefitinib inhibits EGF-stimulated growth of ovarian cancer cells in vitro; this effect is cytostatic, with an increase in apoptosis observed at higher doses and when, used in combination with conventional chemotherapy, producing supraadditive growth arrest. 18,19 Gefitinib also has been tested in xenograft models of ovarian cancer, resulting in inhibitory effects on cell growth and increased survival of mice in the treatment groups. 16,20 Phase I trials of gefitinib in solid tumors, including EOC, have demonstrated tolerable toxicity and promising clinical results.…”

Subcellular Distribution of a Fluorescence-Labeled Combi-Molecule Designed to Block Epidermal Growth Factor Receptor Tyrosine Kinase and Damage DNA with a Green Fluorescent Species

“…The variety of approaches currently used to target EGFR includes small monoclonal antibody strategy to block ligand binding and TK inhibitors (5)(6)(7). Over the past 10 years, molecules that inhibit receptor autophosphorylation and downstream intracellular signaling have been developed and have shown significant antitumor activity in vitro (8)(9)(10)(11)(12).…”

Responses of Human Colorectal Tumor Cells to Treatment with the Anti–Epidermal Growth Factor Receptor Monoclonal Antibody ICR62 Used Alone and in Combination with the EGFR Tyrosine Kinase Inhibitor Gefitinib

“…These discoveries have lead to the strategic development of novel agents targeting the EGFR for the treatment of human malignancies (4). Of these, the two most clinically advanced strategies are the monoclonal antibodies (mAb), which block the extracellular ligand-binding domain, and small molecule tyrosine kinase inhibitors (TKI), which target ATP-binding sites located in the intracellular tyrosine kinase domain of the EGFR (3,5,6). Three such agents, i.e., the anti-EGFR mAb cetuximab (Erbitux), and the TKIs, gefitinib and erlotinib, have now been approved for the treatment of patients with metastatic colorectal cancer and nonsmall cell lung cancer, respectively (5,6).…”

“…Of these, the two most clinically advanced strategies are the monoclonal antibodies (mAb), which block the extracellular ligand-binding domain, and small molecule tyrosine kinase inhibitors (TKI), which target ATP-binding sites located in the intracellular tyrosine kinase domain of the EGFR (3,5,6). Three such agents, i.e., the anti-EGFR mAb cetuximab (Erbitux), and the TKIs, gefitinib and erlotinib, have now been approved for the treatment of patients with metastatic colorectal cancer and nonsmall cell lung cancer, respectively (5,6). Despite objective responses to the EGFR inhibitors in a small fraction of patients, there has been no clear association between the levels of tumor EGFR expression and response to treatment with the EGFR inhibitors (7)(8)(9)(10)(11)(12)(13).…”