# Targeting Endoplasmic Reticulum Stress Sensor IRE1 to Enhance Chemotherapy Sensitivity in MYC-driven breast cancer

> **NIH NIH P50** · BAYLOR COLLEGE OF MEDICINE · 2024 · $342,752

## Abstract

ABSTRACT
Limited sensitivity to chemotherapy and an immunosuppressive tumor microenvironment drives breast cancer 
mortality in HER2 negative breast cancer. We have identified the IRE1/XBP1 branch of the Unfolded Protein 
Response (UPR) or endoplasmic reticulum (EnR) stress response as a previously unexplored therapeutic 
vulnerability in MYC-driven breast cancer that enhances chemotherapy sensitivity and reverses the 
immunosuppressive tumor microenvironment. IRE1 is amplified in ~10% of human breast cancer, and 
frequently co-amplified with the MYC oncogene. Activation of MYC is synthetic lethal with IRE1/XBP1 pathway 
inhibition. We found that inhibition of the IRE1/XBP1 pathway with a highly selective first-in-class IRE1 RNase
inhibitor ORIN1001 suppresses MYC-high-expressing (MYChigh), but not MYC-low-expressing (MYClow), tumor 
growth in patient-derived xenograft (PDX) models. ORIN1001 substantially enhances the docetaxel efficacy, 
resulting in rapid tumor regression and complete eradication of the MYChigh PDX tumors. Furthermore, the 
ORIN1001 plus docetaxel therapy triggers massive cytotoxic T-cell infiltration, depletion of immunosuppressive 
myeloid-derived suppressor cells (MDSCs) and substantial upregulation of PD-L1 in the tumor 
microenvironment. Non-human primate toxicology testing showed that ORIN1001 has excellent safety profile 
and is well-tolerated. These preclinical data prompt us to hypothesize that inhibition of the IRE1/XBP1 pathway 
with the IRE1 inhibitor ORIN1001 compromises MYChigh breast cancers by inhibiting obligatory UPR stress 
adaptation required for cellular viability. This therapeutic effect of ORIN1001 is associated with a marked 
increase in taxane sensitivity. In addition, MDSCs are also selectively depleted by ORIN1001 in the presence 
of a taxane, thus reversing immunosuppression and potentially sensitizing MYChigh breast cancers to immune 
checkpoint intervention. A pre-clinical phase study in breast cancer models will be conducted in parallel with a
Phase 1 clinical trial. In Aim 1, we will establish diagnostic tests to determine eligibility for a clinical trial of 
ORIN1001 plus taxane combination therapy. Aim 2 will exploit the immunomodulatory effects of ORIN1001 
plus docetaxel therapy in breast cancer by testing the addition of anti-PD-L1 immunotherapy. In Aim 3, we will 
conduct a phase I dose escalation study of ORIN1001 alone, then in combination with paclitaxel, followed by 
expansion cohorts in 4 subsets of breast cancer. The overarching objective of this proposal is to design and 
open a Phase 2 clinical trial in MYC-positive metastatic breast cancer with eligibility and endpoints to be 
defined by the execution of the research aims.

## Key facts

- **NIH application ID:** 10928241
- **Project number:** 5P50CA186784-10
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Xi Chen
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $342,752
- **Award type:** 5
- **Project period:** 2014-09-19 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10928241

## Citation

> US National Institutes of Health, RePORTER application 10928241, Targeting Endoplasmic Reticulum Stress Sensor IRE1 to Enhance Chemotherapy Sensitivity in MYC-driven breast cancer (5P50CA186784-10). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10928241. Licensed CC0.

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