Oncology Therapeutic Strategies Targeting Integrated Stress Response

The integrated stress response (ISR) has emerged as a pivotal nexus in the cellular adaptation to a variety of insults, including nutrient deprivation, proteotoxic stress and mitochondrial dysfunction. In cancer cells, chronic activation of the ISR can promote survival under adverse conditions, yet overwhelming this adaptive network tilts the balance towards apoptosis. Modern therapeutic strategies harness this duality by deploying small molecules that selectively amplify stress signals while blocking compensatory pathways. Chief among these is the imipridone class exemplified by ONC201, which engages the mitochondrial protease ClpP to provoke downstream phosphorylation of eIF2α, transcriptional induction of CHOP and upregulation of the death receptor DR5. Concomitant inhibition of survival circuits—most notably the PI3K/Akt axis and anti-apoptotic Bcl-2 family members—enhances tumour cell death and counters metabolic rewiring. Combination regimens are now entering clinical trials in diverse malignancies, with promising signals of efficacy in gliomas, lymphomas and solid tumours. By exploiting the ISR’s capacity to integrate mitochondrial, endoplasmic reticulum and redox cues, these approaches offer a precision framework for selectively eradicating cancer cells while sparing normal tissues.

Research from Nature Portfolio

No recent Nature Portfolio content available.

Oncology Therapeutic Strategies Targeting Integrated Stress Response publication trend

The graph below shows the total number of articles in oncology therapeutic strategies targeting integrated stress response across all publications each year (not limited to Nature Index journals).

Technical terms

Integrated Stress Response (ISR): A conserved signalling network that senses diverse cellular stresses and regulates protein synthesis through eIF2α phosphorylation.

ONC201: A first-in-class imipridone small molecule that activates the ISR by engaging mitochondrial protease ClpP and modulating kinase pathways.

DR5 (Death Receptor 5): A pro-apoptotic receptor for TRAIL, transcriptionally induced by CHOP under ISR conditions.

PI3K/Akt pathway: A major survival and metabolic signalling cascade often upregulated in cancer to counteract stress and promote growth.

Bcl-2 family proteins: A group of pro- and anti-apoptotic regulators controlling mitochondrial outer membrane permeabilisation and cytochrome c release.

References

1. ONC201 in Combination with Paxalisib for the Treatment of H3K27-Altered Diffuse Midline Glioma. Cancer Research (2023).
2. Discovery and clinical introduction of first-in-class imipridone ONC201. Oncotarget (2016).
3. Identification of TRAIL-inducing compounds highlights small molecule ONC201/TIC10 as a unique anti-cancer agent that activates the TRAIL pathway. Molecular Cancer (2015).
4. TIC10/ONC201 synergizes with Bcl-2/Bcl-xL inhibition in glioblastoma by suppression of Mcl-1 and its binding partners in vitro and in vivo. Oncotarget (2015).
5. First-In-Class Small Molecule ONC201 Induces DR5 and Cell Death in Tumor but Not Normal Cells to Provide a Wide Therapeutic Index as an Anti-Cancer Agent. PLOS ONE (2015).