# Identifying Mitophagy Receptors as Targets in Ras-dysregulated Cells

> **NIH NIH P20** · DARTMOUTH COLLEGE · 2020 · $309,043

## Abstract

The five year survival rate for pancreatic ductal adenocarcinomas (PDAC) is approximately 5% making it one 
of the most lethal cancers in the United States. Despite the fact that more than 90% of PDAC contain 
activating mutations within the gene encoding the GTPase KRas, the development of small-molecule 
inhibitors for KRas has only been successful for the G12C allele accounting for 3% of KRAS mutations in 
PDAC. As such, inhibiting pathways which are essential for KRas-driven transformation and tumorigenesis 
may provide a more promising avenue for the development of PDAC targeted therapies. One such pathway 
that is upregulated in response to oncogenic KRas expression encompasses a set of catabolic processes 
termed autophagy. Indeed, a wealth of indicative publications suggest that autophagy could represent an 
Achilles’ heel for certain aggressive and intractable cancers, and inhibitors that globally block autophagy 
have shown some promise in cell culture and mouse models of PDAC. However, therapeutic concentrations 
of these autophagy inhibitors resulted in toxicity. Further translational progress has been hampered by the 
lack of specific reagents: autophagy is actually not a single process but rather a broad family of pathways 
with distinct cargo preferences and mechanisms of recruitment. Recently, oncogenic KRasG12V expression, 
which accounts for 30% of KRAS mutations in PDAC, has been shown to result in the upregulation of a 
specialized form of autophagy, termed mitophagy, in which specific mitophagy receptors mark mitochondria 
for degradation. The goal of this proposal is to determine the role of mitophagy in KRasG12V transformation 
and PDAC. Our central hypothesis is that KRas dysregulation leads to the upregulation of mitophagy to 
promote neoplastic transformation. To test this hypothesis we have developed two specific aims. Aim 1 will 
determine which of the known mitophagy receptors are required for KRasG12V transformation. Furthermore, in 
mammalian cells, many of these pathways are redundant, preventing facile dissection in transformed cells. 
Aim 2 will leverage a novel combination of structural and genetic approaches to identify novel mitophagy 
receptors and cognate interaction partners and thus explore mechanisms of mitophagy in Ras-dysregulated

## Key facts

- **NIH application ID:** 10215731
- **Project number:** 5P20GM113132-05
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** Michael Joseph Ragusa
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $309,043
- **Award type:** 5
- **Project period:** 2016-09-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10215731

## Citation

> US National Institutes of Health, RePORTER application 10215731, Identifying Mitophagy Receptors as Targets in Ras-dysregulated Cells (5P20GM113132-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10215731. Licensed CC0.

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