Lung cancer is the most common cause of cancer death for both women and men. There is therefore a pressing need to improve lung cancer therapy and prevention. This is the subject of this new NIH R01 application in which we now seek to elucidate a previously unrecognized pathway that we found as clinically-tractable in combating lung cancer. Termed anaphase catastrophe, this is caused by targeting the cyclin E-Cdk2 pathway in aneuploidy cancer cells. Neoplastic cells are genetically unstable; strategies that target genome instability are attractive ways to disrupt tumor cell growth and potentially spare normal diploid cells. Chromosome instability (CIN) is genome instability via mitotic defects that increase chromosome mis-segregation. CIN is caused by extra centrosomes that disrupt bipolar spindle assembly needed for faithful chromosome segregation. We found that Cdk2 inhibition prevents centrosome clustering and forces chromosomes to segregate into multiple daughter cancer cells. This triggers apoptosis in aneuploid cells, including lung cancer cells, as will be studied here. Using a robotic cell-based drug screening platform linked to a genetic database, KRAS mutant lung cancer (representing an unmet medical need) cells were exquisitely sensitive to Cdk2 inhibition because they exhibit anaphase catastrophe and apoptosis. CP110 is a centrosome protein and direct Cdk2 phosphorylation target that regulates centrosome clustering. Our hypothesis is: CP110 is the centrosome protein responsible for anaphase catastrophe. Our interdisciplinary team has a long track record of productive collaboration. We have assembled for this work selective Cdk2 inhibitors, clinically-relevant transgenic cyclin E-driven and KRAS-driven mouse lung cancer models and their derived cell lines. A large human lung cancer cell line panel is available as is a paired normal- malignant lung tissue array linked to a clinical database. Our team will use these resources to interrogate these Specific Aims to: (1) learn if CP110 is the critical target of Cdk2 inhibition that antagonizs centrosome clustering and promotes multipolar anaphase to trigger lung cancer cell death; (2) elucidate whether CP110 is the critical mediator of Cdk2-dependent anti-neoplastic effects in lung cancer cells; and (3) establish the biological and clinical relevance of this work using clinically- predictive in vitro, transgenic, and normal-malignant lung tissue banks. Successful completion of these aims would provide a new way to confront lung cancer, the most common cause of cancer death for men and women. This would ultimately identify which lung cancer cases are amenable to Cdk2 inhibition.