PROJECT ABSTRACT Lung cancer is a global scourge responsible for ~1.5 million deaths worldwide, and ~130,000 deaths in the USA in 2022. Despite our understanding of relevant risk factors such as cigarettes, asbestos and radon, lung cancer kills more US citizens than the next four cancer types combined. Although the clinical situation is challenging, fundamental cancer research has revealed that lung cancers can be subdivided into genetically- defined subsets based on driver oncogene mutations that, in turn, serve as predictive biomarkers for the clinical deployment of FDA-approved pathway-targeted therapies in lung cancer patients. In particular, FDA approval of oncoprotein-targeted therapies such sotorasib or dabrafenib plus trametinib as treatments for KRASG12C or BRAFV600E-driven lung cancer respectively are already having an important impact on patients with these subsets of the disease. However, despite this, and recent advances in the deployment of immunotherapy, only a minority of lung cancer patients have benefitted from such advances such that treatment options for many patients remain limited to conventional approaches including surgery, radiation, and/or conventional chemotherapy that are ineffective against tumor cells and toxic to the patient. Consequently, the overarching, long-term goal of this research is to provide a rational scientific foundation for the development of new combination therapeutic strategies to treat patients with KRAS- or BRAF-driven lung cancer that: 1. Increase the overall response rate and depth of each patient's primary response; 2. Maximize safety and tolerability, while minimizing toxicity and; 3. Forestall the onset of lethal drug resistance. To that end, our short-term aims are to elucidate how various signaling pathways cooperate with oncogenic KRAS or BRAF in the genesis and maintenance of lung cancer. To do so we will leverage: 1. State-of-the-art preclinical mouse models (GEM or PDX) of KRAS- or BRAF-driven lung cancer; 2. Human or mouse lung cancer-derived cell lines whose aberrant behavior is driven by relevant genetic abnormalities; 3. Pathway-targeted inhibitors, many of which are FDA-approved or in clinical development and; 4. An outstanding collaborative team of scientists and physicians who will consult on the design, execution and interpretation of the results of our research. Hence, building on a solid foundation of published or preliminary data, we will use models of KRAS- or BRAF-driven lung cancer to elucidate the role of: 1. Autocrine activation of ERBB/HER signaling as a mechanism that promotes lung cancer progression and maintenance; 2. Autophagy as a cytoprotective mechanism that protects lung cancer cells from the cytotoxic effects of pathway-targeted inhibition and; 3. AKT protein kinases as progression factors or pharmacological targets in the genesis or maintenance of lung cancer. Consequently, our research is significant and likely to have lasting and important translational impact in the design and evaluation of new combination pathway- targeted strategies to treat patients with this ubiquitous, devastating and poorly understood disease.

NARRATIVE Lung cancer is a global scourge responsible for 1.5 million patient deaths worldwide, and ~130,000 patient deaths in the USA this year alone. Despite these grim statistics, lung cancer treatment has been revolutionized by the fundamental scientific understanding that lung cancers can be genetically subdivided based on the presence of specific proto-oncogene mutations that, in turn, predict for responsiveness to FDA-approved pathway-targeted therapies. Here, we propose the use of experimental/preclinical models of KRAS- or BRAF-driven lung cancer in combination with inhibitors of cellular signaling pathways to define the importance of key pathways in lung cancer initiation, progression and therapy, with the overarching goal of developing a rational scientific foundation for the development of new combination therapy strategies to more effectively treat lung cancer patients.