Research

Our Research

(Manning and Toker Cell , 2017)

PI3K and AKT Signaling in Cancer

A major focus of the lab is investigating the mechanisms by which the PI 3-kinase and Akt signaling pathway regulates breast cancer progression. Genes in the PI3K pathway harbor some of the most frequent genetic lesions in breast cancer. Our studies have focused on the role of the Akt kinase in modulating breast cancer progression. We have discovered that Akt1 is a breast cancer cell motility and invasion suppressor, while Akt2 is an enhancer of invasive migration and metastatic dissemination. We are testing targeted protein degradation as a method to therapeutically suppress oncogenic Akt signaling, and for use as a tool to investigate kinase-independent functions of Akt. We are currently studying different roles of Akt isoforms, improved strategies to target Akt alone or in rational combinations, and mechanisms of resistance to targeted PI3K and Akt inhibitors. The goal of this work is to deepen our understanding of PI3K/Akt signaling, and to create new treatment strategies for breast cancer with oncogenic PI3K signaling.

Recent Publication Highlights

Parallel phosphoproteomics and metabolomics map the global metabolic tyrosine phosphoproteome

Targeting cholesterol biosynthesis with statins synergizes with AKT inhibitors in triple-negative breast cancer

Multiomic profiling of breast cancer cells uncovers stress MAPK-associated sensitivity to AKT degradation

PI3K drives the de novo synthesis of coenzyme A from vitamin B5

While metabolic enzymes are frequently tyrosine phosphorylated, few of these sites have been functionally characterized. An integrated analysis of phosphoproteomic and metabolomic datasets provides a framework for rapid identification of functionally relevant tyrosine phosphorylation sites on metabolic enzymes. Understanding how phosphorylation regulates metabolic enzyme function will inform both normal and pathophysiological states, highlighting potential new targets in diseases with aberrant tyrosine phosphorylation, such as cancer.

(Hillis et al. PNAS , 2024)

Two FDA-approved compounds, AKT inhibitors and pitavastatin, synergize to induce cell death in triple negative breast cancer, motivating evaluation of the efficacy of this combination in clinical trials.

(Hillis et al. Cancer Res , 2024)

Using multiomic profiling and causal network integration in breast cancer cells, we demonstrated that the enhanced efficacy of the AKT degrader INY-05–040 was associated with sustained suppression of AKT signaling, which was followed by induction of the stress mitogen activated protein kinase (MAPK) c-Jun N-terminal kinase (JNK). Further integration of growth inhibition assays with publicly available transcriptomic, proteomic, and reverse phase protein array (RPPA) measurements established low basal JNK signaling as a biomarker for breast cancer sensitivity to AKT degradation.

(Erickson et al. Sci Signal , 2024)

Our study demonstrates that, in conjunction with metabolite-mediated feedback, PI3K–AKT signalling regulates flux through the de novo CoA synthesis pathway. Our results also reveal a specific cellular function for the highly conserved PANK4, which we propose directly limits the rate of CoA synthesis through its metabolite phosphatase activity against 4′-phosphopantetheine and possibly other related substrates.

(Dibble et al. Nature , 2022)