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Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib
Published on: June 26, 2019
Epidermal growth factor receptor inhibitors in development for the treatment of non-small cell lung cancer
John V Heymach1, Monique Nilsson, George Blumenschein
1Department of Thoracic/Head and Neck Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030-4009, USA. jheymach@mdanderson.org
Abstract:
The epidermal growth factor receptor (EGFR) inhibitors erlotinib, gefitinib, and cetuximab have undergone extensive clinical testing and have established clinical activity in non-small cell lung cancer and other types of solid tumors. A number of newer inhibitors are currently in clinical development with different spectra of activity or mechanisms of receptor inhibition. These include monoclonal antibodies, such as panitumumab and matuzumab; dual inhibitors of EGFR and vascular endothelial growth factor receptor, such as ZD6474 and AEE788; inhibitors of multiple EGFR family members, such as lapatinib; and irreversible inhibitors, such as canertinib and HKI272. Preclinical studies suggest that several of these agents may have activity in tumors refractory to erlotinib or gefitinib. Among these agents, ZD6474 has undergone the most extensive clinical testing. The antitumor activity of ZD6474 in these two randomized phase II clinical trials in patients with non-small cell lung cancer was felt to be sufficiently promising to warrant phase III clinical testing. Several of the other EGFR inhibitors are also undergoing advanced clinical testing, either alone or in combination with other agents. EGFR has now been validated as a clinically relevant target, and several different types of agents inhibiting this receptor are currently in development. Future research will be needed to elucidate the role of these agents in patients with EGFR inhibitor-naive and EGFR inhibitor-refractory disease, to define the molecular characteristics that predict response, and to determine whether these drugs should be used in combination with other targeted agents or chemotherapy.
Insights
New epidermal growth factor receptor (EGFR) inhibitors show promise for treating non-small cell lung cancer and other solid tumors, including those resistant to current therapies. Further research is ongoing to define their role and optimal use.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Epidermal growth factor receptor (EGFR) inhibitors like erlotinib, gefitinib, and cetuximab are established treatments for non-small cell lung cancer (NSCLC) and other solid tumors.
- Resistance to existing EGFR inhibitors necessitates the development of novel therapeutic strategies.
- A diverse range of new EGFR inhibitors with varying mechanisms and spectra of activity are in clinical development.
Purpose of the Study:
- To review the landscape of emerging EGFR inhibitors and their potential clinical applications.
- To highlight agents showing promise in preclinical models of EGFR inhibitor-refractory disease.
- To discuss the ongoing clinical development and future research directions for novel EGFR-targeted therapies.
Main Methods:
- Review of preclinical data and ongoing clinical trials for novel EGFR inhibitors.
- Analysis of different classes of inhibitors including monoclonal antibodies, dual inhibitors, multi-EGFR family inhibitors, and irreversible inhibitors.
- Focus on agents like ZD6474 that have advanced to Phase III clinical testing.
Main Results:
- Several novel EGFR inhibitors, including ZD6474, panitumumab, matuzumab, AEE788, lapatinib, canertinib, and HKI272, are in various stages of clinical development.
- Preclinical studies suggest potential activity of these agents in tumors resistant to first-generation EGFR inhibitors.
- ZD6474 has demonstrated promising antitumor activity in Phase II trials for NSCLC, warranting Phase III investigation.
Conclusions:
- EGFR is a validated therapeutic target, with multiple novel inhibitors under development.
- These new agents offer potential treatment options for both EGFR inhibitor-naive and refractory cancers.
- Future research should focus on identifying predictive biomarkers, optimizing combination strategies with chemotherapy or other targeted agents, and defining the role of these inhibitors in clinical practice.
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