Identification and Characterization of Novel Cancer Genetic Dependencies

Abstract

Cancer cells have unique genetic dependencies that can be exploited therapeutically, leading to successful targeted therapeutic drugs that benefit patients. However, many cancers remain undruggable, and many drug development efforts targeting cancer genetic dependencies have failed. To address these challenges, my thesis work focuses on two specific aspects. First, the paradigm of cancer dependencies and targeted therapies has been largely focused on inhibition of critical pathways in cancer. Conversely, conditional activation of signaling pathways as a new source of selective cancer vulnerabilities has not been systematically characterized. In Chapter 2, I developed a method for enacting gain-of-function genetic perturbations simultaneously across ~500 barcoded cancer cell lines to query the pan-cancer vulnerability landscape upon activating 10 key pathway nodes, revealing selective activation dependencies of MAPK, PI3K, p53, and cell cycle pathways associated with specific biomarkers. Notably, we discovered novel pathway hyperactivation dependencies in subsets of APC-mutant colorectal cancers where further activation of the WNT pathway by APC knockdown or direct β-catenin overexpression led to robust anti-tumor effects in xenograft and patient-derived organoid models. Together, this chapter reveals a new class of conditional gene activation dependencies in cancer. Second, despite remarkable successes in the clinic, cancer targeted therapy development remains challenging and the failure rate is disappointingly high. In chapter 3, I identified that the problem is partly due to the misapplication of the targeted therapy paradigm to therapeutics targeting pan-essential genes, which can result in therapeutics where efficacy is attenuated by dose-limiting toxicity. I summarized the key features of successful chemotherapy and targeted therapy agents, and used case studies to outline recurrent challenges to drug development efforts targeting pan-essential genes. Finally, I suggested strategies to avoid previous pitfalls for ongoing and future development of pan-essential therapeutics.