Lung cancer, the most common subtype of which is non-small cell lung cancer (NSCLC), is the most common cause of cancer mortality in the US. Improved, rational treatments are needed. NSCLC's with activating mutations in the epidermal growth factor receptor (EGFR) often respond to treatment with EGFR tyrosine kinase inhibitors (TKIs) but the magnitude of tumor regression is variable and transient. We hypothesized that the heterogeneity of treatment response may result from genetic modifiers that regulate the degree to which tumor cells are dependent on mutant EGFR and, hence, the magnitude and duration of response to EGFR TKI treatment in patients. Through a pooled RNA-interference (RNAi) screening strategy we found that knockdown of CD95 and several components of the NF-kB pathway specifically enhanced cell death induced by the EGFR TKI erlotinib in EGFR-mutant lung cancer cells. Activation of NF-kB promoted resistance to EGFR TKI in EGFR-mutant lung cancer models. Genetic or pharmacologic inhibition of NF-kB enhanced erlotinib-induced apoptosis in EGFR-mutant lung cancer models. Increased expression of the NF-kB inhibitor IkB predicted for improved response and survival EGFR-mutant lung cancer patients treated with EGFR TKI. These data identify NF-kB as a potential companion drug target, together with EGFR, in EGFR-mutant lung cancers. We propose to further test the hypothesis that the CD95-NF-?B pathway and EGFR are rational companion therapeutic targets in EGFR-mutant lung cancers using pathway-selective NF-?B pharmacologic inhibitors, state-of-the-art murine lung cancer models, and prospectively acquired human lung cancer clinical data in 3 innovative and integrated Specific Aims: 1) Determine the effects of pathway selective pharmacologic inhibitors of NF-kB in EGFR-mutant lung cancer using cellular and in vivo models. Here we will test the hypothesis that pharmacologic inhibition of NF-kB, together with EGFR, will enhance responses in EGFR-mutant lung cancer cellular and murine models. We will also define the mechanisms whereby NF-kB inhibition potentiates cell death induced by EGFR TKI treatment. 2) Determine if CD95-NF-?B signaling is sufficient to induce de novo EGFR TKI resistance in the native tumor environment. Here we will test the hypothesis that selective activation of the CD95-NF-kB signaling axis is sufficient to induce de novo resistance to EGFR TKI treatment in the native tumor environment. We will use transgenic murine models of EGFR-mutant lung cancer in conjunction with transgenic murine models of CD95 ligand that allow for selective activation of CD95 pro-survival output via NF-kB. 3) Determine if increased CD95-NF-?B signaling promotes EGFR TKI acquired resistance in EGFR- mutant lung cancers. Here we will test the hypothesis that increased CD95-NF-kB signaling promotes acquired resistance to EGFR TKI treatment in vivo using both EGFR-mutant lung cancer murine models and prospectively acquired human clinical specimens and data. Our overall goal is to define the strategies for CD95-NF-kB inhibition most likely to be maximally effective in appropriately selected lung cancer patients. !

Public Health Relevance

Lung cancer is a major public health problem because it is the most common cause of cancer-related death in the US. Treatments that specifically target proteins that drive lung cancer growth, such as EGFR inhibitors, are leading to improved responses in lung cancer patients but success is limited because treatment resistance occurs. The studies in this grant proposal focus on the discovery of new mechanisms of resistance to EGFR inhibitors in lung cancer. Findings from our studies will hopefully lead to improved treatments that overcome resistance to EGFR inhibitors by allowing for the design of rational combination therapies. Together our findings will have a major impact on lung cancer by optimizing personalized treatment strategies that will increase the survival of lung cancer patients. !

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
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Forry, Suzanne L
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University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
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