# Role of Sphingolipids in KRAS induced lung adenocarcinoma

> **NIH VA I01** · VA SAN DIEGO HEALTHCARE SYSTEM · 2024 · —

## Abstract

Project Summary/Abstract
We have analyzed Kras mutant lung adenocarcinoma and demonstrated that the cell of origin is
the alveolar Type II cell. Alveolar Type II cells undergo a Notch-dependent dedifferentiation to
bipotent progenitor cells. These cells have markers of both Type I and Type II cells and initiate
and propagate tumors both in vitro and in vivo. Thus, finding methods of inhibiting these cells
could quickly lead to important therapeutic advances for patients with KRAS mutant tumors.
Sphingolipid pathways downstream of Kras are promising therapeutic targets in these cells. In
the current application, we will use mechanistic and high throughput methods to test existing
drugs against 3-dimensional cultures of Kras mutant bipotent progenitor cells. We will also use
Cas/Crispr technology to identify sphingolipid genes and pathways that will be effective in
inhibiting these cells. Finally, because macrophages are intimately involved with the tumor
cells during initiation and progression and sphingolipids are involved in tumor immune
suppression, we will test unique inhibitors of immunosuppressive tumor macrophages and
sphingolipid inhibitors to allow immune surveillance of forming tumors. In addition, additive
mutations of p53 and Lkb1 which are common in lung adenocarcinoma will be used in all assays
so that the broad range of KRAS mutant lung adenocarcinomas will be addressed.

## Key facts

- **NIH application ID:** 10702183
- **Project number:** 1I01BX006097-01A1
- **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM
- **Principal Investigator:** Mark Onaitis
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2024-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10702183

## Citation

> US National Institutes of Health, RePORTER application 10702183, Role of Sphingolipids in KRAS induced lung adenocarcinoma (1I01BX006097-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10702183. Licensed CC0.

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