Lung cancer has very high annual incidence and remains the most lethal cancer with disproportionately high mortality rates in both genders despite current therapy. The recent use of novel molecular targeted drug Tarceva® (erlotinib) in metastatic lung cancer against the cancer-associated protein epidermal growth factor receptor (EGFR) has led to tremendous advances in our understanding of lung cancer genetics and mechanism of response and resistance to the new class of inhibitor drugs. However, the overall patient responses to Tarceva® remains low in the North American patient population, and worse still, all initial responders invariably eventually progress and succumb to resistant recurrent disease. Our research effort has focused on a novel critical cancer-associated target, MET receptor, in lung cancer for treatment, and we not only have defined a number of novel genetic changes in the receptor protein activated in lung cancer, but also characterized the MET inhibitors (SU11274, PHA665752) as novel therapeutics. More recently, we further identified strategy of combinatorial regimen of inhibitors against MET and EGFR to enhance efficacy against Tarceva®-resistant lung cancer that carries resistant mutation (T790M) in EGFR. In our proposal here, we will using a combination of various state-of-the-arts research platforms such as small animal multimodal molecular imaging (bioluminescence, MRI, PET), and also lung tumor xenograft tissues immunohistochemical analysis, to further study a novel MET inhibitor drug XL184 that is currently undergoing clinical trial studies in human cancer. Molecular factors that can help predict response and resistance would be studied in order to help optimize the future personalized MET-based targeted lung cancer therapy. Second, we will also identify signal pathways that determine the cell fates under these targeted inhibitors treatment pressure allowing some cells to survive the initial cellkill.

Our preliminary work already has shed novel insights into the process of early tumor resistant escape against targeted inhibitors and further studies as proposed in our project here aim to dissect the critical molecular determinants of promoting such early tumor resistant escape. Novel targets discovery will be brought forth by our studies that focus on the earliest resistant transformation of tumor cells en route to the eventual late resistance that will be much more heterogeneous and difficult to tackle by the time. We believe that our original approach to emphasize in and investigate within the early time window of targeted therapy will uncover the most vulnerable "Achilles' heel" of the acquired resistant tumor cells, and will render them attractive residual disease targets to be eradicated. Deeper insights into the predicting factors and prognostic factors in novel MET targeted therapeutics such as XL184, and better strategies to eradicate early tumor resistant escape survivor cells will altogether bring forth a new way to treat lung cancer patients with the primes of substantially improve the long-term clinical outcome and survival.