Lung cancer is the leading cause of cancer-related death worldwide. Non-small cell lung cancer (NSCLC) cases account for 85% of all diagnoses, and lung adenocarcinoma (LUAD) is the most common NSCLC subtype. The predominant gain-of-function mutation in LUAD occurs in the KRAS oncogene, representing roughly 30% of cases. Despite this frequency, our current understanding of the cancer-specific mechanisms of KRAS-driven oncogenesis remains limited. Our laboratory is interested in identifying key regulators of oncogenic Kras function with the ultimate goal of identifying novel “synthetic lethal” interactions that could be used for therapy.

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Over the last twenty years, the laboratory has made numerous contributions to the study of KRAS biology.  Using cross-species microarray analysis to compare a mouse model of lung cancer to human disease, we previously uncovered a gene expression profile associated with Kras mutation across species and in different tissues (Sweet-Cordero, et al Nature Genetics 2005). A major effort in our laboratory has been the characterization of synthetic dependencies induced by oncogenic KRAS signaling in lung cancer. We demonstrated that loss of the WT1 protein (Wilm’s tumor suppressor 1) causes senescence in non-small cell lung cancers that express oncogenic KRAS whereas it is largely dispensable in cells expressing wild-type Kras. We have shown that KRAS plays a critical role in regulating the response to nutrient stress. In tumors carrying both a KRAS mutation and KEAP1 loss, nutrient stress leads to apoptosis, identifying a potential combinatorial vulnerability.  Most recently, we co-led a multi-PI effort to map novel KRAS dependencies using proteomics and CRISPR/CAS9 combinatorial screens. This work identified a novel dependency on combined loss of RhoA and RAP1GDS1 in KRAS-driven lung cancer.

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We use tools for genetic analysis (CRISRP, CRISPRi) to identify new vulnerabilities in the Ras pathway. We use genetically engineered tumor models to determine how Ras vulnerabilities are influenced by genetic context.

Projects

Investigating Mechanisms of NOTCH3 Signaling in KRAS-Mutant LUAD

Previous work from our laboratory identified a key role for Notch3 in lung cancer (Zheng et al, Cancer Cell, 2013). Using both in vitro and in vivo models, we are evaluating the role of Notch and Notch ligands in tumor initiation and maintenance.  We use well-characterized GEM models that allow for genetic ablation of members of this pathway using CRISPR/CAS9.  We also use PDX models that can be evaluated for the role of these genes.

Rap1GDS1 as a synthetic vulnerability in the context of KRAS-driven LUAD