PROJECT SUMMARY/ABSTRACT Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality worldwide. The development of targeted molecular therapies that inhibit mutant oncogenic proteins and immunotherapies that inhibit the PD- 1/PD-L1 pathway have improved outcomes for subsets of patients with NSCLC. However, targeted therapies are only effective against NSCLCs that harbor actionable genetic alterations. In addition, anti-PD-1/PD-L1 immune checkpoint inhibitors are most effective against NSCLCs that express high levels of PD-L1 or have a high tumor mutation burden. Thus, patients with NSCLCs that lack these features do not benefit from targeted therapies and are less likely to benefit from immunotherapies, emphasizing the need to identify novel therapeutic targets in this disease. This project seeks to characterize the XRN1 exoribonuclease, which functions in cellular RNA degradation, as a target that may have broad therapeutic potential in NSCLC. My preliminary data show that XRN1 inactivation induces cell lethality in a subset of human NSCLC cell lines. In an implantable mouse tumor model, XRN1 deletion can synergize with anti-PD-1 immunotherapy to enhance tumor eradication. Aim 1 will define the molecular signaling pathways that mediate cell lethality after XRN1 deletion in a subset of human NSCLC cell lines. Aim 2 will assess the impact of XRN1 deletion in mouse NSCLC models of anti-PD-1 immunotherapy. Aim 3 will determine whether XRN1 gene expression in human NSCLC tumors may serve as a predictive biomarker for treatment response to anti-PD-1 immunotherapy. The long-term goals of the proposed research are to gain fundamental insights into how RNA metabolism regulates cancer cell survival and anti- tumor immunity and to establish RNA metabolism pathways as potential therapeutic targets in NSCLC. The applicant, Dr. Tao Zou, is an oncologist at Dana-Farber Cancer Institute (DFCI). He spends 80% of his time engaged in research and career development activities and 20% of his time in clinical practice caring for patients with lung cancer. Dr. Zou has outlined a five-year career development plan that will enable him to achieve his goal of leading an independent laboratory that conducts basic and translational research at the intersection of RNA biology and lung cancer immunotherapy. Dr. Zou will perform the proposed research under the mentorship of Dr. Matthew Meyerson, an expert in lung cancer biology with a strong record of training independent investigators in academic cancer research. Together with expert members of Dr. Zou’s Scientific Advisory Committee, Dr. Meyerson will ensure that Dr. Zou will obtain additional training in innate immune RNA sensing, tumor immunology, translational studies using human biospecimens, and computational biology. Dr. Zou will conduct the proposed research primarily at DFCI and will leverage additional resources available to him at the Broad Institute and Harvard Medical School. DFCI is a rich research community with a distinguished track record of training successful physician-scientists. DFCI provides the ideal environment for Dr. Zou to build his research expertise and engage in career development activities prior to transitioning to an independent academic position.

PROJECT NARRATIVE Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality in the United States and worldwide, underscoring the critical need to identify new therapeutic targets for this disease. This project seeks to define the fundamental mechanisms by which the XRN1 exoribonuclease, an enzyme that functions to degrade cellular RNA, regulates the survival of NSCLC cells and the anti-tumor immune response to NSCLC tumors. The proposed research will determine whether targeting XRN1 may represent a unique and broadly applicable treatment strategy for patients with NSCLC.