# Metabolic adaptation enables cisplatin resistance and inhibits tumor immunity

> **NIH NIH U54** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $228,275

## Abstract

Project 1 SUMMARY
 A clearer understanding of how tumor cells survive the stress of platinum agents and evolve into
therapy resistant populations is essential to overcome treatment failure and maximize both disease control and
survival. Our data demonstrate that HNSCC cell lines with acquired cisplatin resistance reduce glycolytic and
mitochondrial energy production while increasing carbon flux into anabolic pathways. This results in an
enhanced reductive potential (glutathione, NAD(P)H, FADH2) via both glucose and glutamine catabolism
coupled to increased glutathione (GS) peroxidase 2 (GPX2) activity coordinated at a genomic and
transcriptional level, partially through the KEAP1-NRF2 pathway. Hyperactivation of GPX2 concomitantly
likely inhibits NF-κB activation, decreasing chemokine and prostaglandin production by tumor cells— leading
to a suppressive tumor immune microenvironment (TIME) enriched for myeloid derived suppressor cells
(MDSCs) and depleted of cytotoxic tumor infiltrating lymphocytes (TILs). It is our central hypothesis that this
metabolic adaptation is a permissive and required step for acquisition of cisplatin resistance. We
further postulate that this metabolic shift transitions some tumors to an immunologically silent phenotype,
which reduces immune surveillance to compound the aggressive behavior and cross-therapy resistance of
CDDP-treated tumors
 We will first define the critical metabolic steps required for generation of an enhanced reductive state
that supports cisplatin resistance in Aim 1. We will utilize in vitro and in vivo orthotopic HNSCC models to
measure the contribution of glucose and glutamine to GS synthesis in cisplatin resistant tumors and, using
chemical inhibition coupled to shRNA blockade of individual transporters and enzymes, identify the critical
rate limiting metabolic steps for GS synthesis and cisplatin resistance in HNSCC. In Aim 2 we will
determine how GS synthesis and utilization (by GPX2 and non GPX means) are coordinated transcriptionally
at least in part through Nrf2 in order to support cisplatin resistance. In Aim 3 we will test the impact of GS
metabolism via canonical (e.g. NF-kB) and metabolic paracrine signaling on development of a suppressive
TIME.
 Completion of the proposed experiments will: 1) identify suitable targets for ablation of the
enhanced reductive state driving cisplatin resistance in HNSCC and 2) identify metabolic biomarkers which can
be coupled to 13C flux imaging-based measurements to generate real-time readout of tumor treatment
response, and inform a more personalized approach to targeting metabolism to overcome CDDP resistance.
By identifying the critical mechanistic underpinnings of metabolic adaptation, we can generate a paradigm
shift in our capability to both rapidly detect acquisition of resistance to genotoxic stress and to overcome it
using multiple clinically viable approaches. It will further shed light on how acquisition of cisplatin
resistance can impact resp...

## Key facts

- **NIH application ID:** 10917409
- **Project number:** 5U54CA274321-03
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** VLAD C SANDULACHE
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $228,275
- **Award type:** 5
- **Project period:** 2022-09-20 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10917409

## Citation

> US National Institutes of Health, RePORTER application 10917409, Metabolic adaptation enables cisplatin resistance and inhibits tumor immunity (5U54CA274321-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10917409. Licensed CC0.

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