MKC8866 / MannKind, Fosun Pharma - LARVOL DELTA

IRE1 signalinig in Triple Negative Breast Cancer (EACR 2025) - "Material and Omics datasets encompassing mRNA, miRNA, proteins, and metabolic products were generated from the TNBC cell line MDA-MB-231 following treatment with MKC8866, an IRE1 inhibitor, at multiple time points... We focused on identifying novel downstream targets of IRE1/XBP1 and IRE1/RIDD signaling pathways. We believe that our work will aid in deciphering the role of IRE1 in TNBC progression and characterization."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA • ERN1 • XBP1

IRE1 activity regulates tumour and microenvironment cell lineage states while stratifying localised and metastatic prostate cancer (EACR 2025) - "We pharmacologically and physiologically perturbed AR (Charcoal Strip, R1881, Enzalutamide), IRE1 and Stress Responses (MKC8866, Thapsigargin, Tunicamycin, glutamine deprivation) in these lines as well as in P20-11 organoids carrying out single cell (scRNAseq) and bulk RNAseq. We have observed that IRE1 activity plays a crucial role in inflammatory responses, the balance between basal, luminal and club epithelial cell states and the responses of individual tumours to ADT and other therapies. Consequently, IRE1 modulation is worth exploring as differentiation therapy in PCa."

Late-breaking abstract • Metastases • Preclinical • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • ERN1 • XBP1

The activity of the Unfolded Protein Response Transducer IRE1 is a predictor of treatment resistant disease and a proxy of NEPC and RB1-loss like phenotypes (PCF 2024) - "We pharmacologically and physiologically perturbed AR (Charcoal Strip, R1881, Enzalutamide), IRE1 and Stress Responses (MKC8866, Thapsigargin, Tunicamycin, glutamine deprivation) in these lines as well as in P20-11 organoids carrying out single cell (scRNAseq) and bulk RNAseq. We have generated an IRE1-dependent transcriptomic score as proxy of multiple driving biologies (AR, Inflammation, DNA repair, Cell Cycle, EMT), multiple histological features (stroma, varying histological tumour grades, varying benign structures, PIN), and can prognosticate bulk datasets from large cohorts both in localised (TCGA) and metastatic (PCF/SU2C) cohorts (CamCapp, cBIOPORTAL). This score may be used as a tool alongside imaging AI and other multiomic modalities to inform neoadjuvant therapeutic formulations."

Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • ERN1 • RB1 • XBP1

Targeting IRE1α reprograms the tumor microenvironment and enhances anti-tumor immunity in prostate cancer. (PubMed, Nat Commun) - "Consistently, the small molecule IRE1α inhibitor MKC8866, currently in clinical trials, reprograms the TME and enhances anti-PD-1 therapy. Our findings show that IRE1α signaling not only promotes cancer cell growth and survival but also interferes with anti-tumor immunity in the TME. Thus, targeting IRE1α can be a promising approach for improving anti-PD-1 immunotherapy in PCa."

Biomarker • Journal • Tumor microenvironment • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Targeting IRE1α alleviates the immunosuppressive tumor microenvironment in prostate cancer (AACR 2024) - "Furthermore, IRE1α inhibition by the small molecule MKC8866 (ORIN1001) that is in clinical trials significantly enhanced anti-PD-1 checkpoint inhibitor therapy in mice. Our findings indicate that IRE1α not only promotes cancer cell growth and survival, but it also strongly inhibits anti-tumor immunity in the PCa TME."

Biomarker • IO biomarker • Tumor microenvironment • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Innate IRE1α-XBP1 activation by viral single-stranded RNA and its influence on lung cytokine production during SARS-CoV-2 pneumonia. (PubMed, Genes Immun) - "These responses were blunted by the IRE1α inhibitor MKC8866, the TLR8 antagonist CU-CPT9a, and knockdown of TLR8 receptor. In contrast, the IRE1α-XBP1 activator IXA4 enhanced these responses. Based on these findings, the TLR8/IRE1α system seems to play a significant role in the induction of the proinflammatory cytokines associated with severe COVID-19 disease and might be a druggable target to control cytokine storm."

IO biomarker • Journal • CNS Disorders • Infectious Disease • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases • TLR7 • TLR8 • XBP1