Discovery, Regulation and Function of the PI 3-Kinase and AKT Pathway in Cancer

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The phosphoinositide 3-kinase (PI3K) pathway is one of the most frequently deregulated signaling cascades in human cancers, regulating virtually all aspects of tumorigenesis in humans, including initiation, progression and metastatic dissemination. The serine/threonine protein kinase AKT transduces PI3K signals to a plethora of cellular responses that are associated with malignancy, including cell proliferation and growth, survival, cell motility and metabolism. In spite of extensive efforts aimed at decoding the function of PI3K/AKT signaling in cancer, and a multitude of small molecule inhibitors developed and aimed at interrupting one or more enzymes in this pathway, robust therapeutic responses to PI3K or AKT inhibition have to date remained elusive. There is therefore an urgent need to identify previously unappreciated vulnerabilities associated with PI3K/AKT pathway addiction. Over the past two decades, our laboratory has been at the forefront of discoveries on the regulation of AKT downstream of PI3K, as well as identifying mechanisms by which AKT mediates signal relay to cellular phenotypes associated with malignancy. This application builds on our collective experience at deciphering the contribution of PI3K and AKT in cancer with emphasis at discovering, identifying and characterizing vulnerabilities associated with PI3K/AKT pathway addiction. In the proposed projects, we will focus our vision in three major areas of work: 1) targets of PI3K/AKT defined by genetic approaches: we will define targets of AKT that modulate cellular phenotypes using defined CRISPR screens that combine gene targeting with mass spectrometry and functional validation. We will also use new genetic mouse models that recapitulate AKT hyperactivation and evaluate sensitivity to targeted therapies; 2) novel chemical probes and screens targeting AKT: we have generated the first in-class degrader or PROTAC that potently and specifically degrades AKT, and out-performs all current AKT inhibitors. We will use this novel probe to target the AKT pathway in cancer. We will perform synthetic lethal CRISPR screens to uncover targets that when combined with PI3K and AKT inhibitors transform cytostatic responses to cytotoxic ones; 3) regulation of protein glycosylation by PI3K/AKT: we have uncovered an entirely new mechanism by which growth factor and oncogenic signaling through PI3K/AKT/mTOR modulates the N-glycosylation pathway, necessary for proper protein folding in the endoplasmic reticulum (ER). Deregulation of this mechanism leads to induction of ER stress. This is the first identification linking oncogene addition to anabolic carbohydrate metabolism, which we will explore with functional glycomics. The proposed studies not only build on our expertise, they also emphasize the urgent need to obtain detailed new insights into the pleiotropic mechanisms that govern PI3K and AKT signaling in cancer. Our findings will provide an integrated, mechanistic understanding of how oncogenic signaling interfaces with cellular reprogramming and expose cancer-specific vulnerabilities that would ultimately lead to the development of new therapeutic opportunities for cancer.