Eric Haura M.D.

Recipient of the Joan's Legacy/LUNGevity Foundation Lung Cancer Research Grant. Funded equally by Joan's Legacy and the LUNGevity Foundation.

Lay Description

Targeting proteins on the cell surface, called epidermal growth factor receptors (EGFR), is an effective therapy for a subset of lifelong non-smokers who develop lung cancer. Lifelong non-smokers who develop lung cancer have been found to have mutations or alterations in EGFR that results in exquisite sensitivity to drugs such as gefitinib or erlotinib. Unfortunately, while tumor shrinkage can last for one to two years, the tumor cells ultimately become resistant to these drugs resulting in regrowth of the tumor and death of the patient. Our laboratory has been interested in an important set of signaling proteins downstream of EGFR called STAT proteins. These proteins act to communicate signals from EGFR to important genes that control cell growth, cell survival, cell metastasis (spreading), and angiogenesis (new blood vessel formation). We previously demonstrated that eliminating the function of Stat3 results in lung cancer cell death. In addition, our previous work showed that a protein called SRC is important in maintaining Stat3 activity. Our more recent unpublished data shows that lung cancer cells with EGFR mutations have enhanced Stat3 activity. In addition, early experiments with new drugs that inhibit SRC show that these drugs can kill lung cancer cells with EGFR mutations. It is our hypothesis that SRC and Stat3 proteins are ideal targets for cancer therapy in lifelong non-smokers who develop lung cancer resulting from EGFR mutations. We plan a series of experiments using mutant EGFR cell lines to demonstrate that inhibitors of SRC and/or Stat3 can kill these cancer cells and may have additive effect when used in conjunction with EGFR inhibitors such as gefitinib or erlotinib.

Scientific Abstract

Of considerable recent interest in the field of lung cancer has been the finding of mutations in the tyrosine kinase domain of EGFR in patients who have responded to gefitinib or erlotinib. Nearly 20% of NSCLC harbor EGFR mutations and these mutations were more frequent in never smokers than ever smokers and in females versus males. Importantly, mutant EGFR selectively activate Akt and STAT pathways that are important in NSCLC cell survival suggesting that the anti-tumor effects of EGFR inhibitors is mediated in part through inhibition of essential downstream survival signaling pathways such as STATs and Akt. A key pathway downstream of EGFR is Stat3, a member of the Signal Transducers and Activators of Transcription (STAT) family of transcription factors. Stat3 regulates a number of pathways important in tumorigenesis including cell cycle progression, apoptosis, tumor angiogenesis, invasion and metastasis, and tumor cell evasion of the immune system. Our laboratory previously reported that inhibition of Stat3, either directly or indirectly with SRC inhibitors, results in apoptosis in NSCLC cell lines without EGFR mutations. In follow up studies, we investigated genome-wide changes in gene expression in lung cancer cells and identified a number of both known Stat3 targets as well as novel Stat3 target genes/pathways implicated in the “hallmarks of cancer”. We have identified nuclear pStat3 expression in 54% of tumors that was correlated with limited smoking history and a trend towards higher pStat3 expression in adenocarcinomas compared with other tumor histology. Importantly, we found a strong positive correlation between pEGFR and pStat3 expression and an inverse correlation between pStat3 and apoptosis consistent with less apoptosis in tumors expressing high amounts of pStat3. Finally, we have found that cell lines with mutant EGFR have increased levels of activated Stat3 compared to cell lines without mutant EGFR and these cells have enhanced sensitivity to novel small molecule inhibitors of EGFR and SRC. Given the high level of Stat3 activity in NSCLC with EGFR mutations and the importance of Stat3 in oncogenesis, we hypothesize that Stat3 is an excellent molecular target in this subset of NSCLC. Direct or indirect targeting of Stat3 may have potent anti-tumor effects and may be used on combination therapy along with other agents targeting survival signaling pathways in NSCLC. We postulate that this important survival cascade can be inhibited by novel SRC inhibitors that interrupt signaling between mutant EGFR and Stat3.