Correspondence

Pulmonary Adenocarcinomas with Mutant Epidermal Growth Factor Receptors

N Engl J Med 2005; 352:1724-1725April 21, 2005

Article

To the Editor:

Activating mutations of the DNA sequence encoding the catalytic kinase domain of the epidermal growth factor receptor (EGFR) have been shown to underlie responsiveness to gefitinib in some cases of non–small-cell lung cancer.1-3 Oncogenic mutations in growth factor receptors typically result in constitutive signaling, which increases cell proliferation without requiring the growth factor. In contrast, these mutant EGFR proteins require the ligand.1 This observation raises the possibility that the EGFR ligands — epidermal growth factor and transforming growth factor α — are secreted by tumor cells themselves (an autocrine loop) or by surrounding stromal cells (a paracrine loop). Distinguishing between these two models has implications for the design of new treatments.

We used immunohistochemistry to identify the cells that contain epidermal growth factor and transforming growth factor α in a total of 10 formalin-fixed, paraffin-embedded pulmonary adenocarcinomas, 4 with mutant EGFR proteins and 6 without. The four EGFR alterations included the major mutation types: missense mutations within exon 18 (G719C) and exon 21 (L861Q) and deletions within exon 19 (delL747-P753insS and delL747-T751insS). All specimens containing these mutant receptors showed strong expression of both ligands in the tumor cells but not in the surrounding stromal cells (Figure 1Figure 1Autocrine Ligand Expression in Pulmonary Adenocarcinomas.). Similar results were observed in the six cases with wild-type EGFR proteins, in agreement with prior reports.4 Thus, pulmonary adenocarcinomas with EGFR mutations are similar to more common forms of lung cancer, in which autocrine secretion of EGFR ligands by tumor cells stimulates the receptors. The exceptional response of tumors with mutant EGFR proteins to gefitinib most likely results from distinct downstream signaling from the receptor after the ligand binds.5 Our observations raise the possibility that mutations of EGFR arise within a pulmonary epithelial cell that is already secreting epidermal growth factor and transforming growth factor α, thus initiating a proliferative stimulus.

Markus J. Riemenschneider, M.D.
Daphne W. Bell, Ph.D.
Daniel A. Haber, M.D., Ph.D.
David N. Louis, M.D.
Massachusetts General Hospital, Boston, MA 02129
mriemenschneider@partners.org

5 References

1. 1

   Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129-2139
   Full Text | Web of Science | Medline

2. 2

   Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497-1500
   CrossRef | Web of Science | Medline

3. 3

   Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from “never smokers“ and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 2004;101:13306-13311
   CrossRef | Web of Science | Medline

4. 4

   Rusch V, Baselga J, Cordon-Cardo C, et al. Differential expression of the epidermal growth factor receptor and its ligands in primary non-small cell lung cancers and adjacent benign lung. Cancer Res 1993;53:Suppl 10:2379-2385
   Web of Science | Medline

5. 5

   Sordella R, Bell DW, Haber DA, Settleman J. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 2004;305:1163-1167
   CrossRef | Web of Science | Medline

Citing Articles (5)

Citing Articles

1. 1

   Colin J.D. Ross, Hagit Katzov, Bruce Carleton, Michael R. Hayden. (2007) Pharmacogenomics and its implications for autoimmune disease. Journal of Autoimmunity 28:2-3, 122-128
   CrossRef

2. 2

   Bin-Bing S. Zhou, Michael Peyton, Biao He, Changnian Liu, Luc Girard, Eian Caudler, Yvonne Lo, Frederic Baribaud, Iwao Mikami, Noemi Reguart, Gengjie Yang, Yanlong Li, Wenqing Yao, Kris Vaddi, Adi F. Gazdar, Steven M. Friedman, David M. Jablons, Robert C. Newton, Jordan S. Fridman, John D. Minna, Peggy A. Scherle. (2006) Targeting ADAM-mediated ligand cleavage to inhibit HER3 and EGFR pathways in non-small cell lung cancer. Cancer Cell 10:1, 39-50
   CrossRef

3. 3

   BIN-BING S. ZHOU. (2005) Targeting Ligand Cleavage to Inhibit the ErbB Pathway in Cancer. Annals of the New York Academy of Sciences 1059:1, 56-60
   CrossRef

4. 4

   J. D. Minna, M. J. Peyton, A. F. Gazdar. (2005) Gefitinib Versus Cetuximab in Lung Cancer: Round One. JNCI Journal of the National Cancer Institute 97:16, 1168-1169
   CrossRef

5. 5

   D.A. HABER, D.W. BELL, R. SORDELLA, E.L. KWAK, N. GODIN-HEYMANN, S.V. SHARMA, T.J. LYNCH, J. SETTLEMAN. (2005) Molecular Targeted Therapy of Lung Cancer: EGFR Mutations and Response to EGFR Inhibitors. Cold Spring Harbor Symposia on Quantitative Biology 70:1, 419-426
   CrossRef