Bruce E. Johnson, MD
Professor of Medicine, Harvard Medical School
Office phone: 617-632-4790
Preferred contact method: email
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Non-small cell lung cancer, Small cell lung cancer, Genomic characterization, Mesothelioma
Area of ResearchThe impact of genomic changes on the targeted treatment of thoracic malignancies
Dana-Farber Cancer Institute
450 Brookline Avenue
Boston, MA 02215
Dr. Johnson received his MD from the University of Minnesota in 1979 and his postgraduate training at the University of Chicago and the National Cancer Institute. After serving at NCI, where he most recently headed the Lung Cancer Biology Section, he joined DFCI in 1999. He currently directs the Dana-Farber/Partners CancerCare Thoracic Oncology Program, a cooperative effort that includes DFCI, Brigham and Women's Hospital, and Massachusetts General Hospital.
- The ASCO Cancer Foundation Translational Research Professorship, 2008-2013
ResearchThe impact of genomic changes on the targeted treatment of thoracic malignancies
Our research is devoted to testing the efficacy of novel therapeutic agents against lung cancer and other thoracic malignancies. Translational research on patients with adenocarcinoma of the lung has helped identify subsets of patients who respond differently to targeted agents. We found that women, patients with adenocarcinoma (rather than other types of lung cancer), and patients who do not smoke cigarettes are more likely to have a favorable response to treatment with gefitinib and erlotinib (Iressa and Tarceva). These findings prompted our laboratory to create tumor cell lines from women with adenocarcinoma to characterize their response to gefitinib.
In collaboration with Drs. Sellers and Meyerson, we discovered that most patients who responded to gefitinib have either point mutations or deletions of amino acids from the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). Our laboratory then showed that lung cancer cell lines with these point mutations or deletions are 100-fold more sensitive to gefitinib than cell lines with the wild type sequence of the EGFR. Treatment of lung cancer cells having EGFR mutations with 100 nanomolars of gefitinib downregulates phosphorylated EGFR, which, in turn, leads to the downregulation of downstream targets including phospho-Akt and phospho-Erk1/2 kinase. Treatment of lung cancer cells having EGFR mutations with 1 micromolar of gefitinib leads to apoptosis, while the cells with wild type EGFR undergo a G1/S arrest. Future studies will examine the relationship among different mutations in the EGFR, their susceptibility to different EGFR inhibitors, and the EGFR signaling pathways.
Prospective trials are testing the impact of erlotinib treatment on patients with non-small cell lung cancer and EGFR mutations. These studies include previously untreated patients older than 70 with advanced non-small cell lung cancer as well as women with adenocarcinoma who either never smoked or are former smokers. The tumor DNA of these patients is studied for the EGFR sequence, and the rate and duration of patients' response, their subsequent response to other chemotherapy, and their survival are recorded. The purpose of these trials is to determine whether a relationship exists between the EGFR sequence and the outcome of patients with non-small cell lung cancer after treatment with erlotinib.
The laboratory is also studying mechanisms of resistance to epidermal growth factor tyrosine kinase inhibitors. Lung cancer cell lines are exposed to gefitinib and erlotinib and studied. This procedure has confirmed the acquired point mutation, T790M, as a mechanism of resistance both in patients and in a tumor cell line (NCI-3255GR). The studies in our laboratories have also identified amplification of the MET oncogene as a mechanism of reistance in a cell line (HCC827GR) and in patients.
Clinical trials are ongoing to identify agents that are effective in patients whose tumor become resistant to erlotinib and gefitinib. These include different irreversible inhibitors of the epidermal growth factor receptor, inhibitors of HSP-90, and combined epidermal growth factor receptor and MET oncogene inhibition.
- Tracy S, Mukohara T, Hansen M, Meyerson M, Johnson BE, Janne PA. Gefitinib induces apoptosis in the EGFRL858R non-small-cell lung cancer cell line H3255. Cancer Res 2004:64;7241-4.
- Mukohara T, Engelman JA, Hanna NH, Yeap BY, Kobayashi S, Lindeman N, Halmos B, Pearlberg J,Tsuchihashi Z, Cantley LC, Johnson BE, Jnne PA. Differential effects of gefitinib and cetuximab on non-small cell lung cancers bearing epidermal growth factor receptor mutations. J Natl Cancer Inst 2005:97:1185-94.
- Johnson BE, Fischer T, Fischer B, Dunlop R, Silberman S, Kowalski MO, Sayles D, Simitrijevic S, Fletcher C, Hornick J, Salgia R, Le Chevalier TL. Phase II study of imatinib in patients with small-cell lung cancer. Clin Cancer Res 2003;9:5880-7.
- Paez G, 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 WJ, Johnson BE, Meyerson M. EGFR mutations in lung cancer: correlation with clinical response to gefitinib. Science 2004;304:1497-500.
- Heymach VJ, Johnson DH, Khuri FR, Safran H, Schlabach LL, Yunus F, DeVore RF III, De Porre PM, Richards HR, Jia X, Zhang S, Johnson BE. Phase II study of the farnesyl transferase inhibitor R115777 in patients with sensitive relapse small-cell lung cancer. Ann Oncol 2004;5:1187-93.
- Eberhard DA, Johnson BE, Amler LC, Goddard AD, Heldens SL, Herbst RS, Ince WL, Jnne PA, Januario T, Johnson DH, Klein P, Miller VA, Ostland MA, Ramies DA, Sebisanovic D, Stinson JA, Zhang YR, Seshagiri S, Hillan KJ. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol 2005;23:5900-9.
- Jänne PA, Gurubhagavatula S, Yeap BY, Lucca J, Ostler P, Skarin AT, Fidias P, Lynch TJ, Johnson BE. Outcomes of patients with advanced non-small cell lung cancer treated with gefitinib (ZD1839, 'Iressa') on an expanded access study. Lung Cancer 2004;44:221-30.
- Mukohara T, Civiello G, Johnson BE, Jnne PA. Therapeutic targeting of multiple signaling pathways in malignant pleural mesothelioma. Oncology 2005;68:500-10.
- Heymach JV, Johnson BE, Prager D, Csada E, Roubec J, Pesek M, Spasova I, Belani CP, Bodrogi I, Gadgeel S, Kennedy SJ, Hou J and Herbst RS. Vandetanib (ZD6474) plus docetaxel in patients with previously treated non-small cell lung cancer: Results of a randomized, placebo-controlled phase I/II study. J Clin Onc. 2007;25(27) In press.
- Jackman DM, Yeap BY, Lindeman NI, Fidias P, Rabin MS, Temel J, Skarin AT, Meyerson M, Holmes A, Borras AM, Friedlin B, Ostler PA, Lucca J, Lynch TJ, Johnson BE, and Janne PA. Phase II clinical trial of chemotherapy-nave patients > 70 years of age treated with erlotinib for advanced non-small cell lung cancer. J Clin Oncol. 2007; 25(7):760-6.
- Jackman DM, Yeap BY, Sequist LV, Lindeman N, Holmes AJ, Joshi VA, Bell DW, Huberman MS, Halmos B, Rabin MS, Haber DA, Lynch TJ, Meyerson M, Johnson BE and Janne PA. Exon 19 Deletion Mutations of Epidermal Growth Factor Receptor Are Associated with Prolonged Survival in NonSmall Cell Lung Cancer Patients Treated with Gefitinib or Erlotinib. Clin Cancer Res 2006;12, 3908-14.
- Chute J, Taylor E, Williams J, Le PT, Kaye F, Venzon D, Johnson BE. A Metabolic Study of Patients with Lung Cancer and Hyponatremia of Malignancy. Clin Cancer Res 2006;12(3):888-896.
- Mukohara T, Civiello G, David IJ, Taffaro ML, Christensen J. Fisher DE, Johnson BE, Janne PA. Inhibition of the met receptor in mesothelioma. Clin Cancer Res. 2005;15;11(22):8122-30.
- Janne PA, Borras AM, Yanan Kuang Y, Rogers AM, Joshi VA, Liyanage H, Lindeman N, Lee J, Halmos B, Maher EA, Distel RJ, Meyerson M, and Johnson BE. A rapid and sensitive enzymatic method for EGFR mutation screening. Clin Cancer Res 2006;12(3):751-758.
- Engelman JA, Mukohara T, Zejnullahu K, Lifshits E, Borras AM, Christopher-Michael Gale C-M, Naumov GN, Yeap BY, Jarrell E, Sun J, Tracy S, Zhao X, Heymach JV, Johnson BE, Cantley LC, and Janne PA. Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR -amplified lung cancer. J Clin Invest 2006;116:2695-706.
- Jackman, David M., MD
- Gandhi, Leena, MD, PhD
- Ortiz, Taylor, MD
- Heon, Stephanie, MD