Lung cancer is the leading cause of cancer mortality worldwide and lung adenocarcinoma is the most common type. Many cases of lung adenocarcinoma are attributed to a mutation in a gene for the epidermal growth factor receptor (EGFR). Lung cancer with changes in EGFR is initially treatable with a family of chemotherapeutic agents called tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. However, patients often develop resistance to these drugs through the acquisition of additional changes or secondary mutations that allow cancer cells to evade treatment.
Some secondary mutations to the EGFR gene that allow lung cancer cells to survive in the presence of current chemotherapy are known. These secondary changes are now the focus of targeted efforts to create drugs to specifically interfere with the mutated form of the protein. Unfortunately, in 40% of the cases in which patients become resistant to therapy, the molecular events that confer this resistance are not known. Without knowing the changes that sustain the survival of these cells it remains impossible to specifically and effectively target them with anti-cancer drugs.
Scientists now describe a mouse model of lung cancer that develops resistance to TKI drugs in at least some of the same ways that humans do. Lung cancer occurs in these mice due to a mutation in EGFR that is the same as the mutation that underlies many human lung adenocarcinomas. Some of the defined secondary changes to EGFR, which are known to confer drug resistance in humans, also occur in these mice. But most of these drug resistant mice bear tumors that do not contain known mutations. This important similarity to the human situation suggests that this mouse model might help identify the currently unknown mutations that make lung cancer cells resistant to therapy.
Many techniques are now available to unravel the genetic changes that occur in cancer cells. Since these mice recapitulate many of the known mutations that characterize human lung cancer, the hope is that their cells can be screened to identify the currently unknown mutations that promote drug resistance in lung cancer cells. This provides a model to uncover the molecular events responsible for the 40% of patients that become resistant to TKI therapy due to unknown causes. Once novel mechanisms of resistance are identified, these mice might also become valuable preclinical systems to evaluate the efficacy of therapeutics developed to combat drug-resistant disease.
The characterization of mice with drug resistant lung tumors is presented in the Research Report titled 'Erlotinib resistance in mouse models of epidermal growth factor receptor-induced lung adenocarcinoma' and was written by Katerina Politi, Pang-Dian Fan, Ronglai Shen, Maureen Zakowski and Harold Varmus at the Memorial Sloan-Kettering Cancer Center in New York, USA. The study is published in the January/Febuary 2010 issue of the new research journal, Disease Models & Mechanisms (DMM), <http://dmm.biologists.org/>, published by The Company of Biologists, a non-profit based in Cambridge, UK.
About Disease Models & Mechanisms:
Disease Models & Mechanisms (DMM) is a new research journal, launched in 2008, that publishes primary scientific research, as well as review articles, editorials, and research highlights. The journal's mission is to provide a forum for clinicians and scientists to discuss basic science and clinical research related to human disease, disease detection and novel therapies. DMM is published by the Company of Biologists, a non-profit organization based in Cambridge, UK.
The Company also publishes the international biology research journals Development, Journal of Cell Science, and The Journal of Experimental Biology. In addition to financing these journals, the Company provides grants to scientific societies and supports other activities including travelling fellowships for junior scientists, workshops and conferences. The world's poorest nations receive free and unrestricted access to the Company's journals.
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Disease Models & Mechanisms