Biomarker testing to inform treatment planning is the standard of care worldwide for patients with non-small cell lung cancer. However, most patients still do not experience long term survival, due to incomplete responses to initial therapy and acquired resistance. The goal of this proposal is to develop novel therapeutic strategies based on an understanding of the genomic, molecular, and cellular changes involved in treatment response/resistance. Our three objectives are integrated under the premise of discovering new paradigms for mechanism-based therapies, each addressing critical gaps where the current framework for precision medicine falls short. (1) While multiple distinct variants can...

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Biomarker testing to inform treatment planning is the standard of care worldwide for patients with non-small cell lung cancer. However, most patients still do not experience long term survival, due to incomplete responses to initial therapy and acquired resistance. The goal of this proposal is to develop novel therapeutic strategies based on an understanding of the genomic, molecular, and cellular changes involved in treatment response/resistance. Our three objectives are integrated under the premise of discovering new paradigms for mechanism-based therapies, each addressing critical gaps where the current framework for precision medicine falls short. (1) While multiple distinct variants can be detected in a given oncogene, treatment decisions are often made irrespective of which variant is present in the tumor, and there is a paucity of information regarding how individual variants influence protein structure/function. Our objective is to create structure-based classification systems for tumor variants to inform clinical decision making. (2) Current targeted therapeutic approaches in the clinic are limited by incomplete response. Our objective is to define the genomic and proteomic characteristics of drug-tolerant persister cells that escape the cytotoxic effects of oncogene-directed therapies, to develop strategies for overcoming the persister state. (3) Despite the recent emergence of four transcriptionally defined subtypes of small cell lung cancer, the therapeutic implications of these subtypes have not been elucidated, in part due to a paucity of tumor tissue. Our objective is to develop non-invasive approaches to assess subtype plasticity and identify subtype-specific vulnerabilities. Overall, the proposed work will redefine current paradigms for targeting oncogenic kinases and enable biomarker-driven treatments for SCLC. By addressing key outstanding questions, we propose to fundamentally reshape the framework of precision medicine for lung cancer.

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