# BCCMA: The Role of Sphingolipids in the Induction & Maintenance of Non-Small Cell Lung Cancer by Oncogenic KRAS

> **NIH VA I01** · VA VETERANS ADMINISTRATION HOSPITAL · 2024 · —

## Abstract

Lung cancer is the leading cause of cancer death for veterans, and non-small cell lung cancer (NSCLC)
represents the majority with a meager 5-year survival rate of ~23%. New therapeutic strategies are needed,
and elucidation of novel mechanisms controlling the tumorigenicity of NSCLC cells will provide the foundation
upon which to build. In this regard, the KRAS gene is mutated at a high percentage in NSCLC (~35%)
producing an oncogene, and our overarching hypothesis for this collaborative grant is that NSCLC tumors
with oncogenic KRAS require specific perturbations in sphingolipid metabolism to maintain cellular
homeostasis allowing for the genesis of cancer progeniture cells and the development of NSCLC. The
collaborative proposal is entitled, “The role of sphingolipids in the induction & maintenance of non-small cell
lung cancer by oncogenic KRAS”. The overall objectives of our three projects are: 1) Determine how &
when specific perturbations of sphingolipid biosynthesis occur during the formation of lineage cells required for
KRAS-induced tumorigenesis; 2) Determine the translation to human NSCLC; 3) Use OMIC-driven processes
to determine global perturbations in sphingolipid biosynthesis that are KRAS-dependent versus cooperative; 4)
Determine the link between sphingolipid biosynthesis and signaling pathways required for NSCLC formation
induce by the KRAS oncogene; and 5) Determine whether modulation of sphingolipid pathways is a plausible
therapeutic modality for treatment of this oncogenotype. The three projects are highly interactive, share overall
goals, collaborate on specific subaims, & leverage the strengths of each laboratory to achieve these objectives.
 This is Project#1, and we found that ceramide kinase (CERK), and its sphingolipid product, ceramide-1-
phosphate (C1P), were significantly enhanced in human NSCLC tumors and cells with mtKRAS. Genetic
ablation/inhibition of CERK dramatically reduced cell survival in mtKRAS versus wild-type KRAS NSCLC cells.
CERK inhibition synergistically reduced survival in mtKRAS NSCLC cells with standard of care therapeutics,
and CERK genetic ablation blocked tumor formation in the KRAS mouse model of lung cancer. Based on these
data, we hypothesize that mtKRAS NSCLC tumors are addicted to higher levels of CERK-derived C1P, which
are required for lung tumorigenesis and can be targeted to enhance therapeutic outcome (e.g., tailored
therapeutics).
 Mechanistically, mtKRAS NSCLC cells showed high levels of mitochondrial C1P (mitoC1P), and CERK is
also localized to the mitochondria. CERK inhibition induced the novel death mechanism, ferroptosis, in only
mtKRAS NSCLC cells, which was linked to loss of the VDAC1:tubulin interaction and AKT translocation to the
mitochondria. C1P activated AKT to induce a novel direct phosphorylation of VDAC1, and AKT signaling is
linked to VDAC1 phosphorylation (ser57 & thr65) in large mass spectrometric studies. Thus, we hypothesize
that CERK-derived mitoC1P is require...

## Key facts

- **NIH application ID:** 10586208
- **Project number:** 1I01BX006063-01
- **Recipient organization:** VA VETERANS ADMINISTRATION HOSPITAL
- **Principal Investigator:** CHARLES E. CHALFANT
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2023-10-01 → 2027-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10586208

## Citation

> US National Institutes of Health, RePORTER application 10586208, BCCMA: The Role of Sphingolipids in the Induction & Maintenance of Non-Small Cell Lung Cancer by Oncogenic KRAS (1I01BX006063-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10586208. Licensed CC0.

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