# Novel regulation of PI3K/Akt to direct targeted breast cancer therapies

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2022 · $407,313

## Abstract

PI3K/AKT/mTOR signaling is critical for the cancer initiation and progression. Aberrant PI3K/AKT/mTOR
hyperactivation has been documented in a large proportion of breast cancer patients. However, PI3K/AKT
inhibitors have shown limited efficacy in the clinic, due to dose-limiting toxicities and emergence of resistance.
Thus, identification of aberrant mechanisms of upstream regulation of AKT and identification of downstream
mechanisms of PI3K/AKT signal relay to phenotypes associated with malignancy, remains critical.
 Epigenetic regulation plays an important role in tumorigenesis, and inhibitors targeting epigenetic factors are
in clinical trials. Methylation of histones as well as non-histone proteins has been shown to play a functionally
pivotal role in human cancers, including breast cancer. However, whether oncogenic signaling pathways,
including PI3K/AKT/mTOR, are subject to methylation-dependent regulation has not been explored. Our
preliminary data show that AKT undergoes lysyl methylation, a novel mode of regulation that contributes to
protein kinase activation in breast cancer. Depletion of the histone methyltransferase SETDB1 reduces AKT
activity, suggesting that SETDB1 could be a novel therapeutic target for PI3K/AKT-driven breast cancers.
Therefore, in Aim 1 we propose that aberrant expression of SETDB1 in breast cancer contributes to
hyperactivation of AKT in a methylation-dependent manner. We will define mechanistically how SETDB1
functions as a novel upstream regulatory mechanism that promotes AKT activation. We will further examine
whether genetic ablation of SETDB1 suppresses proliferation in vitro and in vivo.
 Gene transcription, protein translation and metabolic reprogramming are known to mediate
PI3K/AKT/mTOR signaling in cancer. Our preliminary studies have uncovered a previously unrecognized
mechanism, whereby the N-glycosyl transferase ALG3 (asparagine-linked glycosylation 3 homolog), is co-
amplified with PIK3CA in breast tumors, tightly correlates with a proliferative gene signature in breast cancers
and is phosphorylated downstream of PI3K/AKT/mTOR. Deregulation of ALG3 induces ER stress leading to
activation of the unfolded protein response (UPR). Thus, in Aim 2, we propose that ALG3 is a functional target
of PI3K/AKT/mTOR/S6K1 signaling, and that hyperactivation of this pathway is required to meet the demands
of increased protein translation, thereby reducing ER stress. We will determine the mechanism by which
PI3K/mTOR signaling regulates ALG3 function and perform functional glycomics in vitro and in vivo. We will
determine the contribution of ALG3 to growth in pathway-mutant cells and use combination therapy
approaches with PI3K/AKT/mTOR inhibitors and drugs that block ER stress/UPR. The proposed studies will
provide the molecular basis and rationale for developing more effective targeted therapies by suppressing the
PI3K/AKT pathway based on individual patients’ signaling signatures to achieve better treatment outc...

## Key facts

- **NIH application ID:** 10390306
- **Project number:** 5R01CA177910-09
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Wenyi Wei
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $407,313
- **Award type:** 5
- **Project period:** 2013-07-16 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10390306

## Citation

> US National Institutes of Health, RePORTER application 10390306, Novel regulation of PI3K/Akt to direct targeted breast cancer therapies (5R01CA177910-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10390306. Licensed CC0.

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