Trends in Molecular Medicine
Mutations and addiction to EGFR: the Achilles ‘heal’ of lung cancers?
Section snippets
Addiction to oncogenes
The EGFR-related pathway is an excellent example of what Bernard Weinstein has termed ‘addiction to oncogenes’ [4]; that is, cancer cells are physiologically dependent on the continued activity of specifically activated or overexpressed oncogenes for the maintenance of their malignant phenotype. Weinstein also pointed out that addiction might also be the Achilles ‘heal’ of cancer; the cancer cell might become more susceptible to therapies that target the addiction. Mutations to the EGFR gene
Protein phosphorylation and kinases
The importance of protein phosphorylation for signaling is indicated by the fact that protein kinase domains are found in ∼2% of eukaryotic genes [5]. All protein kinases catalyze the same reaction: the transfer of the γ-phosphate of ATP to the hydroxyl group of serine, threonine or tyrosine [6]. The serine–threonine kinases and the TKs form a closely related superfamily. The TKs are found only in metazoans, whereas the serine–threonine kinases are present in uni- and multi-cellular organisms
The epidermal growth factor gene and its family
After the discovery of EGF in 1962, EGFR (or ERBB1; erythroblastosis B), the prototypical RTK, was demonstrated to have TK activity in 1980 by Stanley Cohen and coworkers, and sequenced by an international consortium in 1984 9, 10. The discovery that EGFR was the mammalian equivalent of the avian viral oncogene v-erbB demonstrated that RTKs have a crucial role in tumorigenesis. EGFR is the prototypical member of a family of four RTKs, EGFR (ERBB1, HER1), ERBB2 (HER2, Neu), ERBB3 (HER3) and ERBB4
EGFR and cancers
Although germline mutations in receptor TKs are associated with various inherited syndromes [16], TKs historically define the typical class of oncogenes that are involved in many cancer types [7]. Aberrant or increased EGFR expression is found in many cancers. Gene amplification occurs in ∼40% of glioblastomas [17]. In many cases, amplification is accompanied by somatic mutations (or abnormal splice variants). Although a variety of mutations (sometimes multiple) have been described, the most
Tyrosine kinase inhibitors for the treatment of lung cancer
Because of their important role in cancer pathogenesis, RTKs and their ligands are popular rational targets for therapeutic intervention [8]. EGFR is overexpressed in many human cancers and overexpression frequently correlates with poor clinical outcome. In addition, tumors might produce ligands for the receptors, establishing autocrine stimulatory loops. These observations led John Mendelsohn to select EGFR for targeted therapy two decades ago, making it one of the first molecules so selected
The pattern of EGFR mutations
EGFR mutations have been described in brain and other tumors. In general, these are large deletions (or possibly splice variants), usually involving the extracellular domains, that result in a rearranged self-activated gene [17]. They occur within a background of gene amplification which appears to precede mutation [21]. To date, reports of mutations involving the TK domain of the gene have been limited to lung cancer. The mutations target adenocarcinoma histology, female gender, oriental
EGFR, KRAS and the pathogenesis of lung adenocarcinomas
In human cancers, the most common activating mutations are those involving the RAS family of oncogenes, in particular KRAS. In lung cancers, mutations of KRAS also target adenocarcinoma histology, but otherwise differ from EGFR mutations because they are relatively rare in Orientals and occur more frequently in males and smokers 24, 25. These observations led us to predict that EGFR and KRAS mutations target different subsets of lung adenocarcinomas [26]. Findings presented at the recent IASLC
Conclusions: some answers, many questions
The finding of EGFR mutations and the prediction of sensitivity to small-molecule TK inhibitors represent a major step towards the rational selection and treatment of subpopulations of patients with cancer who are most likely to benefit form such therapies. However, although progress within a few short weeks of the discovery has been breathtaking in extent and scope, much remains to be learned.
Concluding remarks
The finding of EGFR mutations represents one of the most important genetic abnormalities in lung cancers that has been described to date, because of the promise of immediate clinical applications [3]. The answers to the questions raised will need to be addressed before we can optimally use the mutational data for clinical care and prevention. Given the rapid pace of work in this area being performed in many laboratories throughout the world, we expect that most of the questions will be answered
Acknowledgements
Supported by grants 5U01CA8497102 from the Early Detection Research Network and Specialized Program of Research Excellence in Lung Cancer Grant P50CA70907, National Cancer Institute, Bethesda, MD.
References (34)
- et al.
The conformational plasticity of protein kinases
Cell
(2002) Epidermal growth factor receptor: mechanisms of activation and signalling
Exp. Cell Res.
(2003)The ErbB receptors and their role in cancer progression
Exp. Cell Res.
(2003)HER2/neu expression in malignant lung tumors
Semin. Oncol.
(2002)RTK mutations and human syndromeswhen good receptors turn bad
Trends Genet.
(2000)Outcomes of patients with advanced non-small cell lung cancer treated with gefitinib (ZD1839, ‘Iressa’) on an expanded access study
Lung Cancer
(2004)Cooking oil fumes and risk of lung cancer in women in rural Gansu, China
Lung Cancer
(2002)EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy
Science
(2004)Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib
N. Engl. J. Med.
(2004)Medicine. Why a new cancer drug works well, in some patients
Science
(2004)
Cancer. Addiction to oncogenes – the Achilles heal of cancer
Science
Comparative genomics of the eukaryotes
Science
The protein tyrosine kinase family of the human genome
Oncogene
The discovery of receptor tyrosine kinases: targets for cancer therapy
Nat. Rev. Cancer
Antibody-mediated EGF receptor blockade as an anticancer therapy: from the laboratory to the clinic
Cancer Immunol. Immunother.
Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer
J. Clin. Oncol.
Epidermal growth factor receptor family tyrosine kinases as signal integrators and therapeutic targets
Cancer Metastasis Rev.
Cited by (277)
The role of psychiatry in quality of life in young patients with non-small cell lung cancer
2022, Brain, Behavior, and Immunity - HealthSynthesis and Photostability of Osimertinib and Its Mesylate
2023, Chemistry Bulletin / Huaxue TongbaoTCR Pathway Mutations in Mature T Cell Lymphomas
2023, Journal of ImmunologyA new machine learning method for cancer mutation analysis
2022, PLoS Computational Biology