Metastatic Non-small Cell Lung Cancer (NSCLC) is almost uniformly fatal, with a median survival of approximately 8-10 months using the most active combination of conventional chemotherapies. Recent treatment strategies for NSCLC have focused on the development of """"""""targeted therapies"""""""" that aim to specifically disrupt critical oncogenic mechanisms. The phosphoinositide 3-kinase (PI3K)/Akt pathway has been highly implicated in a wide range of epithelial cancers including NSCLC. PI3K consists of a dimer between the regulatory subunit, p85, and the catalytic subunit, p110.PI3K is activated upon the binding of p85's SH2 domains to tyrosine-phosphorylated proteins, such as receptor tyrosine kinase (RTKs) or adaptors, at the plasma membrane. Recently, somatic EGFR mutations have been identified in a high proportion of patients with NSCLC who respond to clinically approved EGFR tyrosine kinase inhibitors (TKIs). We and others have shown that, in this unique subset of NSCLC cell lines, EGFR kinase activity is critical for activation of the PI3K/Akt signaling pathway. By immunoprecipitating p85 from EGFR TKIs- sensitive NSCLC cell lines, we discovered that ErbB-3, an EGFR family member, is the major phosphotyrosine protein bound to PI3K and couples EGFR to PI3K activity. Unfortunately, only a small minority of patients with NSCLC responds to EGFR TKIs and those that respond eventually develop resistance. The major goals of this grant are to identify the molecular mechanisms of activation of PI3K in NSCLCs with acquired and ctenovo resistance to EGFR TKIs. The experiments will utilize PI3K immunoprecipitations as was done to identify ErbB-3 as the mediator of PI3K/Akt signaling in EGFR TKIs- sensitive NSCLC cell lines. These studies will be performed on NSCLC cell lines, xenograft tumor models, and clinical specimens. Ultimately, once the pathways leading to PI3K activation are identified, they will be manipulated in vitro and in xenograft tumor models to assess the functional consequences on intracellular signaling cascades and cellular growth and survival. These studies should serve as the basis for future clinical development of therapeutic strategies and provide benefit to public health by improving treatments for lung cancer. These studies are perfectly suited to my career development as a physician scientist in the field of translational thoracic oncology.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA120060-05
Application #
7798571
Study Section
Subcommittee G - Education (NCI)
Program Officer
Myrick, Dorkina C
Project Start
2006-04-05
Project End
2011-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
5
Fiscal Year
2010
Total Cost
$143,775
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Corcoran, Ryan B; Cheng, Katherine A; Hata, Aaron N et al. (2013) Synthetic lethal interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS mutant cancer models. Cancer Cell 23:121-8
Corcoran, Ryan B; Ebi, Hiromichi; Turke, Alexa B et al. (2012) EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov 2:227-35
Turke, Alexa B; Song, Youngchul; Costa, Carlotta et al. (2012) MEK inhibition leads to PI3K/AKT activation by relieving a negative feedback on ERBB receptors. Cancer Res 72:3228-37
Katayama, Ryohei; Shaw, Alice T; Khan, Tahsin M et al. (2012) Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Sci Transl Med 4:120ra17
Yang, Xuemei; Turke, Alexa B; Qi, Jie et al. (2011) Using tandem mass spectrometry in targeted mode to identify activators of class IA PI3K in cancer. Cancer Res 71:5965-75
Faber, Anthony C; Corcoran, Ryan B; Ebi, Hiromichi et al. (2011) BIM expression in treatment-naive cancers predicts responsiveness to kinase inhibitors. Cancer Discov 1:352-65
Sequist, Lecia V; Waltman, Belinda A; Dias-Santagata, Dora et al. (2011) Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 3:75ra26
Qi, Jie; McTigue, Michele A; Rogers, Andrew et al. (2011) Multiple mutations and bypass mechanisms can contribute to development of acquired resistance to MET inhibitors. Cancer Res 71:1081-91
Ebi, Hiromichi; Corcoran, Ryan B; Singh, Anurag et al. (2011) Receptor tyrosine kinases exert dominant control over PI3K signaling in human KRAS mutant colorectal cancers. J Clin Invest 121:4311-21
Katayama, Ryohei; Khan, Tahsin M; Benes, Cyril et al. (2011) Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK. Proc Natl Acad Sci U S A 108:7535-40

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