Article Published in the Author Account of

Hisayuki Shigematsu

Mutations of EGFR in Lung Cancers and Their Implications for Targeted Therapy

Abstract: Iressa, Erbitux, and Tarceva, all targeting EGFR, have recently been approved for cancer treatment. Recent studies demonstrated that certain EGFR mutations caused structural changes of EGFR molecules so that they may bind more tightly to the drugs and predict an increased response to treatment with these drugs.



The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases [enzymes which phosphorylate (add phosphate groups to) tyrosine residues in proteins] is dysregulated in many human cancers and plays important roles in their development and progression. The family has four member molecules: ERBB1/EGFR/HER1 (located on chromosome 7), ERBB2/HER2 (on chromosome 17), ERBB3/ HER3 (on chromosome 12) and ERBB4/HER4 (on chromosome 2). These receptor molecules are composed of an extracellular ligand-binding domain, a transmembrane segment and an intracellular tyrosine kinase domain followed by a regulatory segment. Although tyrosine kinase domains of the family members are highly homologous to each other, they have distinct properties. The binding of a ligand (a small molecule that binds to a receptor) to its specific receptor results in autophosphorylation of specific tyrosine residues of the receptor and triggers the activation of several important downstream signaling pathways.

EGFR and HER2 have been widely studied in many human cancers. Overexpression of EGFR is frequently observed in several human cancers, and gene variants (EGFRvIII) (i.e., increased expression and/or proteins with different amino acid sequences, and potentially different reactivity or even functions) are frequently found in glioblastomas (a form of brain tumor). Over-expression of HER2 is found in a subset of breast and ovarian cancers correlating with poor prognosis. In non-small cell lung cancers (NSCLCs) overexpression of EGFR is frequently observed in squamous cell carcinoma. Overexpression of HER2 has been reported in about 20% of NSCLC, especially in adenocarcinoma, although gene amplification (increased number of gene copies) is relatively rare. Overexpression of this receptor is associated with poor prognosis in NSCLC patients.

The finding that EGFR overexpression is frequent in many human cancers has led to the development of therapies that target this receptor molecule. The promising results of specific kinase inhibitors conform to the concept of “addiction to oncogenes,” describing cancer cells as being physiologically dependent on activated or overexpressed oncogenes for maintenance of the malignant phenotype (Weinstein, 2002). However, as we have postulated, the cancer cell dependency on EGFR is also its Achilles “heal,” providing a mechanism to inhibit tumor growth (Gazdar et al., 2004)

Recent reports of EGFR mutations in lung cancer have generated considerable interest because they predict the sensitivity to commercially available tyrosine kinase inhibitors for EGFR such as gefitinib (Iressa) or erlotinib (Tarceva) therapy (Lynch et al., 2004; Paez et al., 2004; Pao et al., 2004). The EGFR gene consists of 28 exons (protein-coding DNA segments) and encodes a 170-kilodalton glycoprotein (protein with sugar residues attached). Although several missense mutations or deletions of the extracellular domain of EGFR were detected in glioblastomas, to date all somatic mutations in lung cancers were found within the intracellular domain, specifically the first four exons coding for the tyrosine kinase domain (exons 18-21) which consists of two round-shaped lobes (Figure 1). Tyrosine kinase inhibitors compete with the adenosine triphosphate (ATP, a source molecule for the phosphate group in kinase-catalyzed phosphorylation) for binding to the cleft between the lobes and abrogate the catalytic activity of the receptor by inhibiting phosphorylation.

Combined data from published reports (Kosaka et al., 2004; Lynch et al., 2004; Paez et al., 2004; Pao et al., 2004; Tokumo et al., 2004) and the authors’ additional unpublished cases indicated that the mutations consisted of three very different types (Figure 1) and, interestingly, they all target important structures around the ATP-binding cleft of the receptor. Deletions (9-18 nucleotides) in exon 19 accounted for almost half of all the mutations. Missense mutations (change of single DNA base pairs) in exons 18, 20 or 21 were the second most common mutation, especially a single base substitution in exon 21 where a leucine at position 858 is changed to arginine. We propose that these mutations result in similar structural changes causing a shift of the protein axis, narrowing the ATP binding cleft and resulting in both increased kinase activity and sensitivity to tyrosine kinase inhibitors (Gazdar et al., 2004). Cell lines with mutant EGFR proteins show different patterns of tyrosine phosphorylation within the regulatory segment (Sordella et al., 2004). Since these mutant EGFR proteins appear to enhance cell survival (or anti-apoptotic (suicidal) signals, the efficacy of tyrosine kinase inhibitors may result from the inhibition of anti-apoptotic signals.

EGFR mutations are the first known mutations to be found in lung cancers arising in non-smokers, and are more frequent in the Asian population (specifically in those of Oriental ethnicity) and in women (Figure 2). Importantly they are almost entirely limited to the adenocarcinoma subtype of lung cancer (cancer of the cells lining the walls of the airway tracks of lungs), and are absent in neuroendocrine lung tumors (i.e., cells which share certain properties with endocrine and nerve cells) or in other types of cancer. Adenocarcinoma is the most prevalent type of lung cancers (~50% of all U.S. lung cancer cases) in all races and both genders. Although tobacco smoking is the major cause of all lung cancers, adenocarcinoma has a weaker association with smoking compared to the other types. The very different patterns of EGFR mutations in lung cancers suggest that tobacco smoke may not be a major carcinogen for EGFR mutations and that other, as yet, unidentified carcinogen(s) may be responsible. As we have proposed (Gazdar et al., 2004), there are at least two distinct molecular pathways involved in the pathogenesis of lung adenocarcinomas, one involving EGFR mutations in non-smokers and the other involving KRAS (k-ras; a proto-oncogene with point mutations, associated with some cancers) mutations in smokers. Since mutations of the tyrosine kinase domain of EGFR are more frequent in the Asian population and have not been identified in other human cancers, exposure to the possible carcinogen(s) may be more common in certain geographic regions (or in certain environments) and the genetic backgrounds may also be responsible for EGFR mutations.

EGFR mutations are one of the most important genetic alterations in NSCLC, both in terms of epidemiological aspects and clinical applications. To clarify the correlation of mutation status with drug response in clinical practice, EGFR mutational analysis for lung cancer patients being treated with gefitinib or erlotinib as the front line therapy should be performed. Simultaneously, we have to clarify the reasons why some patients with EGFR mutations have no response and some other patients without EGFR mutations do respond to tyrosine kinase inhibitor therapy. Alternative mechanisms include increased gene copy number, ligand expression by tumor cells, interactions with other receptor family members and influences of other downstream signal molecules in the biological pathway. Furthermore, we must also clarify the mechanism of development of resistance to tyrosine kinase inhibitors and tumor relapse that eventually develops in most patients, even in those with an initial dramatic response. Thus, while the identification of EGFR mutations is perhaps the single most important recent discovery in lung cancer, multiple other facts need to be explored before we can optimally “translate” the finding from the bench to the bedside.

References and Further Readings

Gazdar AF, Shigematsu H, Herz J, Minna JD. Mutations and addiction to EGFR: the Achilles “heal” of lung cancers? Trends in Molecular Medicine 10:481-486, 2004.

Kosaka T, Yatabe Y, Endoh H, Kuwano H, Takahashi T, Mitsudomi T. Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications. Cancer Research, in press, 2004.

Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small cell lung cancer to gefitinib. New England Journal of Medicine 350:2129-2139, 2004.

Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497-1500, 2004.

Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, Singh B, Heelan R, Rusch V, Fulton L, Mardis E, Kupfer D, Wilson R, Kris M, Varmus H. Proceedings of the National Academy of Sciences USA 101:13306-13311, 2004.

Sordella R, Bell DW, Haber DA, Settleman J. Gefitinib-Sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 305:1163-1167, 2004.

Tokumo M, Toyooka S, Kiura K, Shigematsu H, Aoe M, Ichimura K, Tsuda T, Tomii K, Yano M, Tabata M, Ueoka H, Tanimoto M, Date H, Gazdar AF, Shimizu N. The relationship between epidermal growth factor receptor (EGFR) mutations and clinico-pathological features in non-small cell lung cancers. Clinical Cancer Research, in press, 2004.

Weinstein IB. Cancer. Addiction to oncogenes — the Achilles “heal” of cancer. Science 297:63-64, 2002.

[Discovery Medicine, 4(24):444-447, 2004]

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