Functional screening to define apoptosis-inducing precision cancer therapies

Abstract

Cancer is a diverse set of diseases characterized by genetic and epigenetic alterations that permit growth across diverse environmental contexts. The last decade has led to an explosion of sequencing efforts to define the molecular drivers of proliferation across cancers. This effort has led to the development of small-molecule inhibitors that can block oncogenic drivers and the signaling pathways driving growth. These so called “targeted therapies” have led to better progression-free survival in patients. Despite this early success, it has become clear that with few exceptions, all patients treated with targeted therapies will ultimately relapse. Thus, there is an imminent need to define combination strategies that can be employed to suppress intrinsic or acquired resistance in cancer. Here, we combine functional screening approaches, both pharmacological and genetic, to define apoptosis-inducing precision cancer therapies. Specifically, we utilize a pharmacological screening approach to uncover that breast cancers rely on Mcl-1 and Bcl-XL for survival, and that we can leverage mTOR’s translational control over Mcl-1 to induce apoptosis in PIK3CA mutant breast cancers. Additionally, we utilize CRISPR-Cas9 loss-of-function screening to define the landscape of therapeutic cooperativity in KRAS -driven cancers across diverse tissue types. Further, we leverage this landscape to define principles to rationally design combination therapies to suppress resistance. Lastly, in an effort to define targeted therapeutic strategies for cancers that lack traditional oncogenic drivers, we utilized a pharmacological screening approach to define vulnerabilities associated with dysregulated mitochondrial dynamics proteins in cancer. Collectively, our work has demonstrated the power of functional screening approaches to define apoptosis-inducing anti-cancer precision therapies that combat intrinsic and acquired resistance.