# ER stress-driven IRE1a-XBP1 signaling in lung cancer

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $630,307

## Abstract

Abstract
FDA approved molecularly targeted therapies have not significantly reduced mortality in non-small
cell lung cancer (NSCLC) patients. Therefore, identification and characterization of novel targets
for developing effective therapies is warranted. In this proposal, we will develop endoplasmic
reticulum (ER) sensor IRE1 as a potential therapeutic target in NSCLC. Adverse conditions in
the tumor microenvironment (TME) can rapidly disrupt the protein folding capacity of the ER,
thereby triggering a state of cellular “ER stress”. The ER stress response arm of the unfolded
protein response, particularly the conserved IRE1-XBP1 pathway has emerged as a central
orchestrator of malignant progression. Activated during periods of ER stress, the IRE1 RNAse
domain cleaves its downstream target X-box binding protein (Xbp1) mRNA (inactive, XBP1u),
converting it to active isoform (XBP1s), which serves as a functionally active transcription factor.
We have determined that increased expression of XBP1s is associated with poor survival in
NSCLC, cancer cell-intrinsic deletion of IRE1 delayed malignant progression and extended
survival in mouse models of NSCLC. IRE1 deficiency triggered protective type-I IFN responses
associated with marked reprogramming of both the lymphoid and myeloid cell subsets. These
findings have led to the hypothesis that dysregulated IRE1-XBP1s signaling in cancer cells
facilitates NSCLC progression by governing key immunomodulatory programs in the tumor
microenvironment (TME). Therefore, understanding the underlying mechanisms has the potential
to generate unique therapeutic strategies against difficult to treat NSCLC.
We will determine mechanisms by which persistent activation of ER stress sensor IRE1 drives
immunosuppression in the TME (Aim 1), determine if pharmacological inhibition of IRE1α
sensitizes NSCLC to PARP inhibitors, and STING agonists by enhancing type-I IFN responses
(Aim 2), and assess the clinical relevance of a novel IRE1 gene signature in predicting treatment
outcomes in human NSCLC (Aim 3). This proposal is conceptually and technically innovative as it
seeks to investigate for the first time how cancer cell-intrinsic IRE1α activation drives
immunosuppression in the TME that facilitates immune evasion by disrupting cDC1 function and
blunting type-I IFN responses. We expect that the mechanistic insights from these studies will
generate unique translational opportunities that may lead to the design of future clinical trials with
clinical grade IRE1 inhibitors.

## Key facts

- **NIH application ID:** 10770504
- **Project number:** 5R01CA271619-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Juan R Cubillos-Ruiz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $630,307
- **Award type:** 5
- **Project period:** 2023-02-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10770504

## Citation

> US National Institutes of Health, RePORTER application 10770504, ER stress-driven IRE1a-XBP1 signaling in lung cancer (5R01CA271619-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10770504. Licensed CC0.

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