Research Projects

Mutant p53 is a primary oncogenic driver in over 50% of human cancers, including Non-Small Cell Lung Cancer (NSCLC), conferring aggressive phenotypes and therapeutic resistance. Direct targeting of mutant p53 has proven exceptionally challenging, creating a critical need for alternative strategies. This project leverages the principle of synthetic lethality, which aims to exploit unique dependencies in cancer cells that arise from specific genetic alterations. Our rationale is that the loss of wild-type p53 function fundamentally reshapes cellular pathways, creating a reliance on compensatory mechanisms that, if inhibited, can selectively kill cancer cells while sparing healthy tissue. Through an unbiased analysis of the Cancer Dependency Map (DepMap) project, we identified a novel and unexplored vulnerability: the selective essentiality of Ubiquitin-like Modifier Activating Enzyme 6 (UBA6) in p53-mutant cancer cells. Our central hypothesis is that the loss of wild-type p53 function creates a specific dependency on the UBA6-mediated protein modification pathway. We posit that inhibiting UBA6 function will be synthetically lethal in p53-mutant/null cancers, representing a novel therapeutic axis. Our preliminary data strongly supports this, showing that UBA6 knockdown profoundly inhibits the growth of p53-mutant cells and that the loss of p53 function is sufficient to induce this dependency. To test this model, we will pursue three main objectives. First, we will rigorously establish UBA6 as a synthetic-lethal gene in TP53-mutant NSCLC. This will be achieved by systematically silencing UBA6 using shRNA/siRNA in a panel of isogenic p53-wild-type and p53-mutant/-knockdown NSCLC cell lines and assessing impacts on cell proliferation, apoptosis, and cell cycle progression. Second, we will delineate the underlying molecular mechanism of this dependency. We will investigate how UBA6 inhibition impacts protein homeostasis, DNA damage response, and other critical pathways in the p53-mutant context, focusing on the unique UBA6-USE1-FAT10 signaling cascade. Third, we will develop and validate targeting strategies by designing and developing small molecular inhibitor for UBA6 in preclinical models. This will involve testing the efficacy of UBA6 inhibition in cell lines and subsequently in in-vivo mouse xenograft models of p53-mutant NSCLC to evaluate tumor growth suppression and therapeutic potential. The significance of this project is transformative. If our objectives are reached, we will validate UBA6 as a first-in-class, druggable therapeutic target for the largest genetically defined patient population in oncology. This research moves beyond well-explored areas like DNA damage response inhibitors to target a unique node in the ubiquitin-proteasome system, promising high specificity and a potentially wider therapeutic window. Successful completion will not only provide a new, biomarker-driven paradigm for treating intractable p53-mutant cancers but also deliver invaluable chemical probes to dissect UBA6 biology. Ultimately, this work aims to address a critical unmet need, with the potential to change the standard of care for a vast number of cancer patients.