The role of paxillin in tumor malignancy, drug resistance and clinical outcome in lung cancer

Lung cancer is the leading cause of cancer death worldwide. Cigarette smoking is considered to be the major etiological factor for lung cancer development. However, 65% and 96% of male and female lung cancer patients in Taiwan are life time nonsmokers. Therefore, etiological factors other than cigarette smoking may contribute to lung cancer development in Taiwan. As we know, DNA repair capability in nonsmokers with lung cancer is lower than smokers with this disease. Therefore, nonsmokers are expected to have higher chemosensitivity than smokers when patients received chemotherapy. However, during the past three decades, 5-year survival rate of Taiwanese patients (~15%) was similar with patients from Caucasian. This reflects the possibility that different clinical strategy in nonsmokers with lung cancer as compared with smokers should be established for increasing the response to chemotherapy or targeting therapy and consequently improving patients’ prognosis. The response rate of clinical therapy for lung cancer patients are ranged from 20% to 30%. Most patients who received chemotherapy or targeting therapy are died from disease relapse and drug resistance. To enhance the drug sensitivity, reduction of drug resistance, and blocking tumor recurrence, the potentially targeting molecule – paxillin (PXN) has been chosen based on our previous report and preliminary data. PXN overexpression has been shown to promote soft agar growth and invasion capability in lung cancer cells. In addition, lung cancer patients with high PXN tumors had shorter overall survival (OS) and relapse free survival (RFS) than with low PXN tumors. Our preliminary data further showed that PXN overexpression promoted cisplatin resistance via upregulation of BCL-2 due to activation of EGFR/SRC/ERK signaling pathway. Cisplatin and gemcitabine are commonly used in chemotherapy in lung cancer patients. In addition, EGFR-TKI (gefitinib) has been recommended as a first line drug to treat with nonsmoking female lung cancer patients because ~50% patients harbored EGFR mutations. However, the resistance to gemcitabine or gefitinib is frequently occurred in these patients who received both drug treatments. In the first year, we will explore: (1) Whether PXN overexpression could cause the resistance to gemcitabine or gefitinib in lung cancer cells? (2) Which BCL-2 family protein could be upregulated by PXN overexpression? (3) Which signaling pathway(s) could be responsible for upregulation of BCL-2 family proteins by PXN overexpression? (4) Whether upregulation of BCL-2 family proteins by PXN overexpression could be responsible for the resistance to gemcitabine or gefitinib? and (5) the underlying mechanism of PXN overexpression in lung tumor progression and metastasis will be explored to understand whether the signaling pathway activated by PXN overexpression could be responsible for tumor malignancy in lung cancer cells. In the second year, three animal models (subcutaneous xengraft, tail-vein injected metastatic xenograft, and lung orthotropic implantation) will be conducted to explore whether the possible signaling pathway inhibitor(s) combined with gemcitabine or gefitinib could more effective to suppress tumor growth and metastasis in these three animal models when compared with possible signaling pathway inhibitor(s), gemcitabine or gefitinib alone. The possible efficient combined treatment in animal models could have the potential to clinical trial in lung cancer patients with high PXN tumors. Our preliminary data showed that PXN mRNA expression was positively correlated with its protein expression in lung tumors from lung cancer patients. In addition, PXN mRNA levels in plasma/serum were also correlated with it PXN mRNA expression in lung tumors from lung cancer patients. Therefore, in the third year, we would investigate whether PXN mRNA expression in plasma/serum could be useful to predict the response to chemotherapy or EGFR-TKI target therapy in lung cancer patients. We also assess whether PXN mRNA could be used to predict the risk of disease relapse and prognosis in lung cancer patients who received chemotherapy or EGFR-TKI target therapy. In summary, the results from this proposal may be helpful to establish a new combined therapeutic strategy to reduce drug resistance and tumor relapse and consequently to improve clinical outcome and life quality.