# Elucidating the Role of PI3K Lipid Effectors in BRAF Mutant Melanoma

> **NIH NIH F31** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2021 · $35,078

## Abstract

PROJECT ABSTRACT
Metastatic melanoma accounts for the highest number of skin cancer deaths, and stage IV melanoma currently
has only a devastating 15-20% five-year survival rate. This highlights the critical need for new therapeutics
to treat this complex disease. The PI3K/AKT pathway and RAS-RAF-MEK-ERK pathway play a major role in
melanoma initiation and progression. Mutations in BRAF are found in around 50% of all human melanomas,
and although there has been significant success in the development of BRAF mutant melanomas, most
patients will experience primary or secondary resistance. Furthermore, mutant BRAF has been shown to be
insufficient for melanomagenesis, yet the mechanism by mutationally activated BRAF cooperates with
oncogenes and loss of tumor suppressors to promote melanoma tumorigenesis and progression is not well
understood. Dysregulated PI3K/AKT signaling is frequently observed concurrently with BRAF mutant
melanomas though AKT pharmacological inhibitors have been largely ineffective in clinical trials as single
agents. Studies in our lab have shown that there is a discordant effect between pharmacological inhibition and
genetic targeting of AKT, suggesting that therapeutic inhibition of this protein kinase is insufficient to block its
activity in melanoma. We have shown that genetic knockdown of all three AKT paralogs leads to complete cell
lethality in multiple human melanoma cell lines, and overexpression of each of the AKT proteins is able to
significantly rescue this deleterious effect, dependent on functional kinase activity. Based on these preliminary
results, we seek to answer if the PI3K pathway depends solely on AKT signaling for its role in melanoma
initiation and progression. Furthermore, to date, we have also identified additional downstream PI3K lipid
binding proteins that may compensate for the inhibition of the AKT signaling axis in this disease. We
hypothesize that when AKT is inhibited, there are other PI3K lipid effectors, namely SGK, highly homologous to
AKT, that are sufficient for downstream signaling leading to melanoma formation, progression, and metastasis.
The validation of these lipid effectors may lead to additional therapeutic targets. Currently, the field lacks
effective rational combination MAPK and PI3K pathway-targeted therapeutics to more effectively target BRAF
mutated melanomas, and our objective is to uncover the molecular mechanisms of the concurrent activation of
these crucial signaling pathways. Results accumulated from the study will lead to further findings that in turn
will improve the health of melanoma patients, including expanding the average life span after diagnosis.

## Key facts

- **NIH application ID:** 10202447
- **Project number:** 5F31CA254307-02
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Gennie L Parkman
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $35,078
- **Award type:** 5
- **Project period:** 2020-07-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10202447

## Citation

> US National Institutes of Health, RePORTER application 10202447, Elucidating the Role of PI3K Lipid Effectors in BRAF Mutant Melanoma (5F31CA254307-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10202447. Licensed CC0.

---

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