# Interrogating the RAS interactome for therapeutic vulnerabilities

> **NIH NIH K99** · DUKE UNIVERSITY · 2021 · $96,756

## Abstract

PROJECT SUMMARY AND ABSTRACT
The RAS genes KRAS, NRAS, or HRAS, are commonly mutated in human cancers. Clinically
inhibiting RAS has proven challenging and RAS-mutant cancers remain some of the most
intractable diseases, even to immunotherapies. It is thus critical to elucidate oncogenic RAS
signaling, not only to better understand the tumorigenic process, but also to identify new potential
therapeutic targets. To this end, I exploited the novel technique of BirA-mediated proximity
labeling to identify proteins within the immediate vicinity (interactome) of each RAS isoform. I then
screened an sgRNA library targeting interactome components for genes promoting RAS
transformed cell growth, identifying the druggable phosphatidylinositol phosphate lipid kinase
PIP5K1A as specifically driving KRAS oncogenesis. PIP5K1A represents an entirely new
therapeutic target in KRAS-mutant cancers, and suggests that other proteins in the RAS
interactome may similarly mediate RAS oncogenesis. I will capitalized on these discoveries in
three aims. As PIP5K1A is a druggable kinase it provides a way to specifically inhibit KRAS
oncogenesis, which could be exploited to enhance the antineoplastic activity of drugs targeting
RAS effector pathways. Thus, in aim 1 I will elucidate the role and therapeutic potential of
targeting PIP5K1A in KRAS-mutant cancers. The identification of PIP5K1A promoting KRAS
oncogenesis suggests that other interactome proteins may similarly mediate RAS function. Thus,
in aim 2 I will mine the RAS interactome for novel modifiers of RAS oncogenesis, focusing on the
interactome protein EFR3A as a potential general mediator of oncogenic RAS-driven
tumorigenesis. Finally, the RAS interactome is most certainly dynamic, varying under different
conditions. Determining the content of the RAS interactome under distinct settings may thus
identify new vulnerabilities specific to diverse cellular conditions. Thus, in aim 3 I will probe the
RAS interactome in response to cellular perturbations. In sum, I will expand upon my discovery
that PIP5K1A promotes KRAS oncogenesis to explore this kinase as a new therapeutic target and
identify other novel therapeutic vulnerabilities that exists within the RAS interactome. The K99
segment of this grant will complete my training in RAS signal transduction, extend my training
into phosphoproteomics, xenograft and genetically engineered mouse models of tumorigenesis.
The R00 segment will capitalize on the use of proximity labeling to study the dynamic
nature of oncogenic RAS signaling. My long-term goal is to transition into an independent
investigator and apply systems biology approaches to uncover the signaling circuitry of
oncogene drivers with the objective of identifying novel therapeutic vulnerabilities in RAS-mutant
cancers.

## Key facts

- **NIH application ID:** 10124347
- **Project number:** 5K99CA248495-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Hema Adhikari
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $96,756
- **Award type:** 5
- **Project period:** 2020-03-10 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10124347

## Citation

> US National Institutes of Health, RePORTER application 10124347, Interrogating the RAS interactome for therapeutic vulnerabilities (5K99CA248495-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10124347. Licensed CC0.

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