# Class III PI3K as an Autophagy Reactivation Switch in Malignant Transformation

> **NIH NIH K00** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $71,604

## Abstract

Project Summary
 Macroautophagy (hereafter autophagy) is crucial to cellular homeostasis. In healthy cells, high
levels of basal autophagy are necessary for proper homeostasis and are required for anticancer
immunosurveillance. Malignant transformations can arise when autophagy is impaired. Autophagic
activity is low until the tumor outpaces its available nutrient supply. As the tumor outgrows its blood
supply, the environment become hypoxic, and autophagy re-activation is necessary for tumor
proliferation and invasion. Pharmological inhibition of autophagy by antimalarial drug chloroquine leads
to tumor regression, however, this drug is not specific to cancerous cells and has many off-target paths.
This dual role of autophagy in cancer complicates our ability to target it therapeutically. It is unknown
how autophagic function is restored, and this is a central question in the field.
 All autophagy activation mechanisms involve the lipid kinase class III phosphatidylinositol 3-kinase
complex I (PI3KC3-C1) containing tumor suppressor protein BECN1. PI3KC3-C1 is a central initiator,
however, its activation mechanism is unknown and this makes it a challenging enzyme to target
therapeutically. Discovery of the activation mechanism, at the atomic level, of this central lipid kinase
complex through cryo-electron microscopy will greatly aid the ability to rationally design therapeutics to
selectively activate or inhibit PI3KC3-C1 at various stages in cancer transformation or proliferation.
To identify large-scale changes in the proteome during autophagy reactivation in SILAC (Stable
Isotope Labeling with Amino acids in Cell culture) coupled with mass spectrometry will be
performed. The objective here is to determine if there is a unique target in proliferating tumors,
dependent on a specific autophagy activation mechanism or on a selective autophagy pathway.
Ideally, this study would produce new protein candidates to target therapeutically, which would
be more specific and less toxic than hydroxychloroquine to treat pancreatic cancers.

## Key facts

- **NIH application ID:** 10017921
- **Project number:** 5K00CA223029-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Lindsey N Young
- **Activity code:** K00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $71,604
- **Award type:** 5
- **Project period:** 2019-09-13 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10017921

## Citation

> US National Institutes of Health, RePORTER application 10017921, Class III PI3K as an Autophagy Reactivation Switch in Malignant Transformation (5K00CA223029-04). Retrieved via AI Analytics 2026-06-08 from https://api.ai-analytics.org/grant/nih/10017921. Licensed CC0.

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