Currently there will be an estimated 170,000 new cases of lung cancer diagnosed annually, and lung cancer will remain the leading cause of cancer deaths . The present treatment of locally advanced and metastatic lung cancer is very unsatisfactory, and the overall.5-year survival of patients diagnosed with lung cancer is only about 15%. The disappointing results of recent studies have led to the realization that we have reached a """"""""chemotherapy efficacy plateau"""""""". A recent analysis of trials performed over the last 30 years also clearly demonstrated that only minimal progress has been made in the treatment of this disease. It has recently been shown that activating mutations in the Epidermal Growth Factor Receptor (EGFR) tyrosine kinase domain determine responsiveness to the therapies utilizing EGFR tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, in Non-small cell lung cancer (NSCLC) patients. Despite the dramatic responses to the TKIs in certain subsets of NSCLC patients, resistance to the TKIs does emerge over time primarily due to a T790M secondary mutation in the tyrosine kinase domain. Whereas the T790M mutation likely accounts for half the tumors with acquired resistance to TKIs, other mechanism(s) by which resistance to the TKIs emerges are not known. In addition, although we have showed that an alternative, irreversible anilinoquinazoline EGFR inhibitor, CL-387,785, appears to overcome the resistance, new strategies of treatment are sorely needed, considering that novel resistant mutations against the irreversible EGFR inhibitors should occur in the long run and most of NSCLC patients are not curable unless the tumors are detected in an early-stage. Thus, our goals in this proposal are: 1) to clarify the mechanisms for the growth advantage of the T790M secondary mutation 2) to identify novel EGFR mutations in order to elucidate mechanisms of tyrosine kinase inhibitor resistance 3) to develop a novel therapy which could apply to NSCLC patients who do not respond to TKIs. These studies will lead to new insights into mutant EGFR-driven tumorgenesis, as well as the identification of novel target pathways for therapeutic intervention in the future.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Transition Award (R00)
Project #
5R00CA126026-05
Application #
8115164
Study Section
Special Emphasis Panel (ZCA1-RTRB-A (M1))
Program Officer
Forry, Suzanne L
Project Start
2007-07-01
Project End
2013-03-31
Budget Start
2011-08-01
Budget End
2013-03-31
Support Year
5
Fiscal Year
2011
Total Cost
$241,530
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Cai, Yi; Hirata, Ayako; Nakayama, Sohei et al. (2015) CCAAT/enhancer binding protein ? is dispensable for development of lung adenocarcinoma. PLoS One 10:e0120647
Nakayama, Sohei; Sng, Natasha; Carretero, Julian et al. (2014) ?-catenin contributes to lung tumor development induced by EGFR mutations. Cancer Res 74:5891-902
Yamaguchi, Norihiro; Lucena-Araujo, Antonio R; Nakayama, Sohei et al. (2014) Dual ALK and EGFR inhibition targets a mechanism of acquired resistance to the tyrosine kinase inhibitor crizotinib in ALK rearranged lung cancer. Lung Cancer 83:37-43
Kobayashi, Susumu; Canepa, Hannah M; Bailey, Alexandra S et al. (2013) Compound EGFR mutations and response to EGFR tyrosine kinase inhibitors. J Thorac Oncol 8:45-51
Yasuda, Hiroyuki; Park, Eunyoung; Yun, Cai-Hong et al. (2013) Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer. Sci Transl Med 5:216ra177
Yasuda, Hiroyuki; de Figueiredo-Pontes, Lorena L; Kobayashi, Susumu et al. (2012) Preclinical rationale for use of the clinically available multitargeted tyrosine kinase inhibitor crizotinib in ROS1-translocated lung cancer. J Thorac Oncol 7:1086-90
Yasuda, Hiroyuki; Kobayashi, Susumu; Costa, Daniel B (2012) EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications. Lancet Oncol 13:e23-31
Will, Britta; Siddiqi, Tanya; Jordà, Meritxell Alberich et al. (2010) Apoptosis induced by JAK2 inhibition is mediated by Bim and enhanced by the BH3 mimetic ABT-737 in JAK2 mutant human erythroid cells. Blood 115:2901-9
Costa, Daniel B; Kobayashi, Susumu; Yeo, Wee-Lee et al. (2010) Serum concentrations of Erlotinib at a dose of 25 mg daily. J Thorac Oncol 5:1311-2
Zhang, Zhenfeng; Stiegler, Amy L; Boggon, Titus J et al. (2010) EGFR-mutated lung cancer: a paradigm of molecular oncology. Oncotarget 1:497-514

Showing the most recent 10 out of 13 publications