# Mechanistic dissection and inhibitor targeting of autophagy in RAS driven cancers

> **NIH NIH R37** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $446,895

## Abstract

Autophagy is a self-degradation process whereby cells can orderly clear defective organelles and recycle
macromolecules as a nutrient source. Autophagy is elevated and essential for the tumorigenic growth of KRAS-
mutant pancreatic ductal adenocarcinoma (PDAC), providing the rationale for clinical evaluation of the autophagy
inhibitor hydroxychloroquine (HCQ) for PDAC. Disappointingly, when used as monotherapy or in combination
with standard of care, HCQ has shown limited to no clinical efficacy for PDAC. We recently determined that the
treatment of PDAC with inhibitors of the key KRAS effector pathway, the RAF-MEK-ERK mitogenic activated
protein kinase (MAPK) cascade, unexpectedly caused further elevation of autophagy, rendering PDAC acutely
dependent on this process, and hypersensitive to autophagy inhibition. We determined that ERK inhibition
impaired other critical processes that then led to compensatory upregulation of autophagy. Our findings, together
with essentially identical conclusions by another independent co-published study, have led to the initiation of
clinical trials evaluating either MEK (trametinib, binimetinib) or ERK (LY3214996) inhibitor in combination with
HCQ for metastatic KRAS-mutant PDAC. While early observations from compassionate use of this combination
support a significant clinical impact, our preliminary studies support our premise that we can improve upon this
therapy. We propose three aims to further advance autophagy inhibition as an anti-RAS therapeutic approach.
First, we will determine if the ERK MAPK + HCQ combination will be similarly effective in KRAS/NRAS/BRAF-
mutant CRC (Aim 1). HCQ is a lysosome inhibitor and consequently not selective for autophagy. We hypothesize
that inhibitors of the ULK1/2 serine/threonine protein kinases, key initiators of starvation-induced autophagy, will
act as more specific autophagy inhibitors. However, as with all protein kinase inhibitors, inhibitor-induced
compensatory mechanisms will promote resistance to ULK inhibitor efficacy. Additionally, a comprehensive
determination of ULK1/2 substrates remains to be completed. Thus, we will determine the direct and
compensatory effects of ULK inhibition on the phosphoproteome and kinome to critically evaluate ULK inhibitors
as autophagy inhibitors (Aim 2). Our Aim 3 studies are based on our application of a 2,500-gene druggable
genome CRISPR/Cas9 genetic-loss-of-function screen to identify genes that modulate CQ anti-tumor activity.
The identified hits that either enhance or reduce CQ growth inhibition activity represent candidate combinations
or biomarkers for CQ resistance, respectively. We have identified mediators of the DNA damage response and
cell cycle regulators as two major classes of resistance-promoting genes. We will mechanistically dissect these
relationships and determine how inhibition of members of these pathways influences autophagic flux. In
summary, our studies will enhance our understanding of autophagy regulati...

## Key facts

- **NIH application ID:** 10200721
- **Project number:** 5R37CA251877-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Kirsten L Bryant
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $446,895
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200721

## Citation

> US National Institutes of Health, RePORTER application 10200721, Mechanistic dissection and inhibitor targeting of autophagy in RAS driven cancers (5R37CA251877-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10200721. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*