# Mechanisms that control the progression from premalignant lesions to adenocarcinomas in the lung

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $313,000

## Abstract

Oncogenic K-Ras triggers cellular senescence by raising intracellular levels of reactive oxygen species. K-Ras-
expressing cells need to bypass the oncogene-induced senescence (OIS) barrier to progress to higher grades
of malignancy. Non-small cell lung cancer (NSCLC) is the most common form of lung cancer and
adenocarcinoma is the most common type of NSCLC. K-Ras mutations represent the most common molecular
change in lung adenocarcinomas. Progression from pre-malignant lesions to malignant adenocarcinomas is a
hallmark of NSCLC pathogenesis. Our proposed investigations will directly address Provocative
Question #1 by identifying and functionally characterizing novel molecular mechanisms that control the
transition from premalignant lung lesions to adenocarcinomas and whose inhibition has the potential to prevent
NSCLC development.
Central hypothesis: we advance the novel paradigm that caveolin-1 controls the fate of lung epithelial
cells in response to oncogenic Ras. We propose that oncogenic K-Ras induces senescence in premalignant
lung lesions through a caveolin-1-mediated pro-oxidative signaling and that downregulation of caveolin-1
expression is necessary to bypass OIS and drive the progression to malignant adenocarcinomas.
This hypothesis will be tested by pursuing three specific aims:
Aim 1: Determine how caveolin-1 promotes oncogenic K-Ras-induced cellular senescence. Hypothesis:
inhibition of MTH1 function by caveolin-1 is promoted by oncogenic K-Ras via mTOR activation, which leads to
enhanced purine oxidation, sustained DNA damage response (DDR) and cellular senescence in lung epithelial
cells.
Aim 2: Identify how oncogenic K-Ras-expressing cells bypass OIS. Hypothesis: a selective pressure exists
in oncogenic K-Ras-expressing cells that downregulates caveolin-1 gene expression to elude OIS.
Aim 3: Determine if a lack of caveolin-1 promotes the progression to adenocarcinomas in mouse
models of oncogene-induced lung cancer. Hypothesis: Caveolin-1-mediated OIS is a tumor suppressor
mechanism: the genetic ablation of caveolin-1 inhibits the formation of premalignant and senescent-positive
lung lesions in favor of malignant and senescent-negative adenocarcinomas.
These investigations propose the novel concept that targeting K-Ras-dependent signaling that bypasses OIS
through downregulaton of caveolin-1 expression, which will be identified in this proposal, is an alternative and
better therapeutic option then targeting K-Ras itself: it will allow the selective inhibition of pro-tumorigenic K-
Ras signaling while rescuing pro-senescent K-Ras pathways. This new information has the potential to directly
impact the development of novel therapeutic interventions to prevent the progression to lung
adenocarcinomas.

## Key facts

- **NIH application ID:** 10112193
- **Project number:** 5R01CA205165-05
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** FERRUCCIO GALBIATI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $313,000
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10112193

## Citation

> US National Institutes of Health, RePORTER application 10112193, Mechanisms that control the progression from premalignant lesions to adenocarcinomas in the lung (5R01CA205165-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10112193. Licensed CC0.

---

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