# Mechanisms of Resistance to mTOR Targeted Therapies

> **NIH VA I01** · VA GREATER LOS ANGELES HEALTHCARE SYSTEM · 2023 · —

## Abstract

The broad objective of this proposal is to investigate the intrinsic mechanisms of tumor
cell resistance to newly developed mTOR inhibitors such that their future use may be optimized
in the clinic. We have identified an alternate mechanism of mRNA translation initiation that is
activated upon mTOR inhibitor exposure allowing tumor cell survival in the face of global
inhibition of protein synthesis. These experiments will delineate the molecular mechanisms
promoting activation of this salvage pathway and will pre-clinically evaluate the repurposing of
an FDA-approved drug as a small molecule inhibitor targeting this pathway for synergistic
antitumor effects in combination with mTOR inhibitors. We will utilize a combination of genetic
and biochemical approaches to address the mechanisms by which the salvage protein
synthesis pathway is activated in TOR inhibitor resistant brain and breast cancers. We will
utilize mouse models of these diseases to evaluate the efficacy of these inhibitors.

## Key facts

- **NIH application ID:** 10579603
- **Project number:** 2I01BX002665-09A2
- **Recipient organization:** VA GREATER LOS ANGELES HEALTHCARE SYSTEM
- **Principal Investigator:** JOSEPH F GERA
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2014-07-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10579603

## Citation

> US National Institutes of Health, RePORTER application 10579603, Mechanisms of Resistance to mTOR Targeted Therapies (2I01BX002665-09A2). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10579603. Licensed CC0.

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