The highly selective and oral phosphoinositide 3-kinase delta (PI3K-δ) inhibitor roginolisib induces apoptosis in mesothelioma cells and increases immune effector cell composition

Our plain-English summary of The highly selective and oral phosphoinositide 3-kinase delta (PI3K-δ) inhibitor roginolisib induces apoptosis in mesothelioma cells and increases immune effector cell composition, by C. Kalla, G. Ott, F. Finotello, et al (Translational Oncology, 2024).

The study

• Authors: C. Kalla, G. Ott, F. Finotello, K. Niewola-Staszkowska, G.D. Conza, M. Lahn, L. van der Veen, J. Schüler, R. Falkenstern-Ge, J. Kopecka, C. Riganti
• Journal: Translational Oncology
• Published: 2024;43:101857
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Targeting aberrantly expressed kinases in malignant pleural mesothelioma (MPM) is a promising therapeutic strategy. We here investigated the effect of the novel and highly selective Phosphoinositide 3-kinase delta (PI3K-δ) inhibitor roginolisib (IOA-244) on MPM cells and on the immune cells in MPM microenvironment. To this aim, we analyzed the expression of PI3K-δ by immunohistochemistry in specimens from primary MPM, cell viability and death in three different MPM cell lines treated with roginolisib alone and in combination with ipatasertib (AKT inhibitor) and sapanisertib (mTOR inhibitor). In a co-culture model of patient-derived MPM cells, autologous peripheral blood mononuclear cells and fibroblasts, the tumor cell viability and changes in immune cell composition were investigated after treatment of roginolisib with nivolumab and cisplatin. PI3K-δ was detected in 66/89 (74%) MPM tumors and was associated with reduced overall survival (12 vs. 25 months, P=0.0452). Roginolisib induced apoptosis in MPM cells and enhanced the anti-tumor efficacy of AKT and mTOR kinase inhibitors by suppressing PI3K-δ/AKT/mTOR and ERK1/2 signaling. Furthermore, the combination of roginolisib with chemotherapy and immunotherapy re-balanced the immune cell composition, increasing effector T-cells and reducing immune suppressive cells. Overall, roginolisib induces apoptosis in MPM cells and increases the antitumor immune cell effector function when combined with nivolumab and cisplatin. These results provide first insights on the potential of roginolisib as a therapeutic agent in patients with MPM and its potential in combination with established immunotherapy regimen.

Copyright © 2024. Published by Elsevier Inc.

In plain English

This laboratory study examined a protein, PI3K-delta, and an experimental drug that blocks it, roginolisib, in malignant pleural mesothelioma. It did not study asbestos exposure. Archived tumor samples from 89 patients showed moderate or strong PI3K-delta staining in 74% (66/89). Among 51 patients with survival data, median overall survival was 12 months with moderate/strong staining versus 25 months with negative/weak staining (P = 0.0452). In three mesothelioma cell lines, roginolisib reduced cell viability by 34-60%. In the two lines tested for how the cells died (PXF698 and PXF1752), it triggered apoptosis (programmed cell death). Adding drugs that block AKT or mTOR reduced viability further. The authors also built a model combining patient tumor cells, lung fibroblasts and immune cells from the same patients' blood. In it, roginolisib alone or with cisplatin and nivolumab increased cytotoxic CD8+ T-cells and reduced regulatory T-cells. The authors concluded the results support using roginolisib in combination therapies for mesothelioma. They noted that the strongest cell-line effects occurred at 100 µM, a concentration they said would be beyond clinical relevance.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (preclinical) study: immunohistochemistry of retrospectively collected archived tumor specimens with survival comparison, cell-line drug experiments, a patient-derived co-culture model, and computational analysis of public RNA-sequencing data (TCGA)
• Who was studied: Resection specimens from 89 patients diagnosed with malignant pleural mesothelioma (methods list 8 sarcomatoid, 65 epithelioid, 16 biphasic), with survival data for 51. Also studied: three patient-derived xenograft cell lines (PXF698, PXF1118, PXF1752), two patient-derived cell lines (420 and 353) from the Biological Bank of Mesothelioma in Alessandria, Italy, and RNA-sequencing data from 87 primary mesothelioma samples in TCGA. Study dates are not given.
• Exposure: No asbestos exposure was studied. The exposures were laboratory drug treatments: roginolisib (0.1-100 µM in cell lines; 0.025 µM in co-cultures), alone or combined with ipatasertib (AKT inhibitor), sapanisertib (mTOR inhibitor), cisplatin (5 µM) and nivolumab (1 µg/ml). Idelalisib was used for comparison.
• Main results:
  • Moderate or strong PI3K-delta staining was found in 74% (66/89) of patient tumor samples.
  • Patients with moderate/strong PI3K-delta expression had shorter overall survival than patients with negative/weak expression: 12 vs 25 months, P = 0.0452. Survival data were available for 51 patients (14 no/low, 37 moderate/high).
  • In all three cell lines (PXF698, PXF1118, PXF1752), roginolisib reduced cell viability by 34-60%, regardless of histological subtype.
  • The type of cell death caused by roginolisib was investigated in two cell lines only, PXF1752 and PXF698.
  • In PXF698 cells, roginolisib produced a pattern of apoptotic cell death. End-point testing showed PXF698 and PXF1752 cells accumulating in early apoptosis.
  • Combining roginolisib or idelalisib with ipatasertib or sapanisertib inhibited cell viability more than each drug alone.
  • Idelalisib impaired mesothelioma tumor cell growth more than roginolisib.
  • In the patient-derived co-culture, 72 hours of roginolisib reduced tumor cell viability by 75-80%.
  • Fibroblasts protected tumor cells: with fibroblasts, cisplatin/nivolumab had 15% efficacy compared with 50% without fibroblasts.
  • In the co-culture (two independent experiments), roginolisib alone or with cisplatin/nivolumab increased cytotoxic CD8+ T-lymphocytes and M1 macrophages and reduced regulatory T-cells, M2 macrophages and granulocytic myeloid-derived suppressor cells.
  • In 87 TCGA mesothelioma samples, PIK3CD gene expression was not correlated with regulatory T-cell abundance. It showed a weak but significant positive correlation with CD8+ T-cells and M2 macrophages.
  • Up-regulated PI3K-delta together with at least one AKT isoform was seen in 75% (61/81) of patient tumors. PI3K-delta together with mTOR was seen in 20% (17/84).
• The authors' conclusion: The authors concluded that PI3K-delta is widely expressed in malignant pleural mesothelioma and that the study provides evidence to support using roginolisib in combination therapies for mesothelioma and other malignancies.
• Limitations the authors state:
  • Effects in cell lines were most significant at 100 µM, so some inhibition of PI3K-beta may have contributed to the effect.
  • Such high roginolisib concentrations would be beyond clinical relevance.
  • Drug exposure in the laboratory was limited to 72 hours, whereas patients receive the drug over several weeks.
  • The TCGA gene-expression analysis used a small cohort of tumors.
  • The cell lines expressed PI3K-delta at lower levels than primary tumors.

Topics

Medical terms in this study, explained in our Lexicon: Apoptosis, Mesothelioma, Pleural Mesothelioma, Immunohistochemistry, Fibroblast, Nivolumab (Opdivo), Cisplatin, Overall Survival.

Related studies

• Asbestos-induced apoptosis is protein kinase C delta-dependent — A. Shukla, M. Stern, et al. (2003)
• Deficiency of Fyn protein is prerequisite for apoptosis induced by Src family kinase inhibitors in human mesothelioma cells — R. Eguchi, S. Kubo, et al. (2012)
• Proteasome Inhibitor MG132 Induces Apoptosis and Inhibits Invasion of Human Malignant Pleural Mesothelioma Cells — B.Z. Yuan, J.A. Chapman, et al. (2008)
• Novel acridine-based agents with topoisomerase II inhibitor activity suppress mesothelioma cell proliferation and induce apoptosis — A. Raza, B.A. Jacobson, et al. (2012)
• TRAIL and proteasome inhibitors combination induces a robust apoptosis in human malignant pleural mesothelioma cells through Mcl-1 and Akt protein cleavages — B.Z. Yuan, J. Chapman, et al. (2013)
• A phase I pharmacokinetic and pharmacodynamic study of the oral mitogen-activated protein kinase kinase (MEK) inhibitor, WX-554, in patients with advanced solid tumours — D. Jamieson, M.J. Griffin, et al. (2016)

Browse more research in Translational Oncology, or return to medical research.