New Insights into the Unfolded Protein Response Pathway as a Target for Treating Bone Weakness in Cancer Patients

Recent research emphasizes the significant role of the unfolded protein response (UPR) pathway in bone health and cancer-associated bone damage. Proteins must be properly folded in the endoplasmic reticulum (ER) for cell function, but disruptions in this process—known as protein homeostasis—can overwhelm the ER, triggering the UPR to slow protein production and prevent cellular stress. If ER stress persists, it can lead to programmed cell death.

In cancer cells, the UPR pathway often becomes dysregulated, allowing malignant cells to survive in harsh tumor environments characterized by low oxygen and nutrients. This dysregulation also impacts bone tissue, contributing to structural weakening and increased fracture risk.

Researchers Prof. Sarah A. Holstein and Dr. Molly E. Muehlebach from the University of Nebraska Medical Center have extensively studied how the UPR influences bone cell differentiation, maintenance, and how it is hijacked by cancer cells to cause bone deterioration. Their review, published in Bone Research, highlights the connection between UPR pathways—like EIF2AK3, ERN1, and ATF6—and the progression of cancer-induced bone damage, including in cancers such as osteosarcoma, Ewing sarcoma, multiple myeloma, and metastases from breast or prostate cancer.

Bone health relies on a delicate balance of osteoblasts (bone-forming cells) and osteoclasts (bone-resorbing cells). Cancer can disrupt this balance through UPR-related dysfunction, leading to conditions known as skeletal related events (SREs), which result in bones being either too weak or too brittle.

Emerging therapies aim to mitigate SREs by targeting components of the UPR pathways. Potential approaches include inhibiting key proteins like EIF2AK3 and ERN1, supporting protein folding with chaperones, and disrupting tumor cell survival mechanisms. Many of these experimental drugs are in preclinical or early clinical stages and show promise in reducing bone complications and tumor growth.

Prof. Holstein emphasizes the importance of developing selective agents that target cancer and bone tissue specifically, minimizing impact on healthy cells. The ultimate goal is to harness UPR modulation as a viable strategy for treating cancer-associated bone disease, improving patient quality of life and survival.

This research sheds light on new pathways for therapeutic intervention and offers hope for more effective management of bone health in cancer patients. Further investigation is essential to translate these findings into safe and effective treatments.

source: https://medicalxpress.com/news/2025-09-unfolded-protein-response-pathway-bone.html