# Role of ER stress-driven IRE1α-XBP1 Signaling in Lung Cancer Pathogenesis

> **NIH NIH F31** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $45,520

## Abstract

Abstract
Mutant KRAS driven non-small cell lung cancer (NSCLC), confer a dismal 5-year survival rate of
only 15-20%. Despite this clinical significance, there is a lack of an effective targeted therapy for
the treatment of KRAS lung cancer. Given this unmet clinical need, my goal is to investigate the
endoplasmic reticulum (ER) stress response, particularly the protumorigenic IRE1α-XBP1
signaling pathway as an untapped resource of novel targets for therapy development. The
protumorigenic role of ER stress response is being explored in various tumor types. However,
this pathway had not been investigated properly in lung cancer. To first establish the clinical
relevance, I analyzed a tissue microarray of >300 NSCLC clinical samples, and showed
activated XBP1 in both the cancer and the stromal cells. Consistent with these observations,
XBP-1 activation was observed in both the cancer cells and in the intratumoral dendritic cells,
associated with activation of downstream genes in mutant Kras, p53-/- preclinical model of lung
cancer. These preliminary findings, have led to the hypothesis that the aberrant IRE1α-
XBP1signaling axis may contribute to carcinogenesis. Using genetic approaches
(CRISPR/RNAi), and compartment-restricted recombinase systems (Clec9a-Cre or CD11c-Cre),
I will investigate the cell-specific roles of IRE1α-XBP1 signaling in tumor growth, metastatic
capacity and survival. Perturbation of IRE1α/XBP-1 in tumor-infiltrating DCs will be used to
assess their role in T-cell-mediated anti-tumor immunity, as this may provide key insights into
whether XBP-1 targeting would enhance the efficacy of immune checkpoint blockade inhibitors.
Finally, the therapeutic potential of targeting the IRE-1-XBP1 pathway in NSCLC will be
accomplished using selective pharmacological inhibitors of IRE1α. This study has a potential to
yield targets of prognostic and therapeutic value in the IRE-1-XBP1 pathway in KRAS lung
cancer, which represents >30% of lung adenocarcinomas.

## Key facts

- **NIH application ID:** 10238734
- **Project number:** 5F31CA217032-04
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Michael Joseph Crowley
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2017-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10238734

## Citation

> US National Institutes of Health, RePORTER application 10238734, Role of ER stress-driven IRE1α-XBP1 Signaling in Lung Cancer Pathogenesis (5F31CA217032-04). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10238734. Licensed CC0.

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