Lung cancer patients have a poor overall survival rate, with 16% of non-small cell lung cancer (NSCLC) and 6% of SCLC patients surviving over 5 years. Despite the fact that new novel molecular targeted therapeutics have recently come to fruition in the treatment of lung cancers, invasion and metastasis remains an overwhelming problem. The cytoskeleton, especially the actin binding proteins, play an important role in invasion and metastasis. Paxillin is one of the key actin binding proteins which localizes to focal adhesions and interacts with several proto-oncogenes such as E6, v-src, and BCR-ABL. The genetic alteration of paxillin gene and its functional role in cancer have previously not been investigated. Here we show overexpression of paxillin in advanced stage and metastatic tumor as compared to early stage and primary tumors. Novel mutations of paxillin were identified in various cancers with the highest frequency in large cell lung carcinomas (18%). Mutations were clustered to the LIM domains and N-terminus SH2 and SH3 binding region, excluding the LD motifs. A127T mutation was the most frequent and correlated with F-actin stress fiber formation, association with Bcl-2, cell survival, growth and invasion (also in vivo mouse model). Paxillin overexpression, amplification and mutation may contribute to mechanisms of cancer growth and invasion.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA