Inhibition of the PI3K/mTOR Pathway in Breast Cancer to Enhance Response to Immune Checkpoint Inhibitors in Breast Cancer.

Abstract

OBJECTIVES:

Inhibition of the PI3K/mTOR pathway suppresses breast cancer (BC) growth, enhances anti-tumor immune responses, and works synergistically with immune checkpoint inhibitors (ICI). The objective here was to identify a subclass of PI3K inhibitors that, when combined with paclitaxel, is effective in enhancing response to ICI.

METHODS:

C57BL/6 mice were orthotopically implanted with syngeneic luminal/triple-negative-like PyMT cells exhibiting high endogenous PI3K activity. Tumor growth in response to treatment with anti-PD-1 + anti-CTLA-4 (ICI), paclitaxel (PTX), and either the PI3Kα-specific inhibitor alpelisib, the pan-PI3K inhibitor copanlisib, or the broad spectrum PI3K/mTOR inhibitor gedatolisib was evaluated in reference to monotherapy or combinations of these therapies. Effects of these therapeutics on intratumoral immune populations were determined by multicolor FACS.

RESULTS:

Treatment with alpelisib + PTX inhibited PyMT tumor growth and increased tumor-infiltrating granulocytes but did not significantly affect the number of tumor-infiltrating CD8+ T cells and did not synergize with ICI. Copanlisib + PTX + ICI significantly inhibited PyMT growth and increased activation of intratumoral CD8+ T cells as compared to ICI alone, yet did not inhibit tumor growth more than ICI alone. In contrast, gedatolisib + ICI resulted in significantly greater inhibition of tumor growth compared to ICI alone and induced durable dendritic-cell, CD8+ T-cell, and NK-cell responses. Adding PTX to this regimen yielded complete regression in 60% of tumors.

CONCLUSION:

PI3K/mTOR inhibition plus PTX heightens response to ICI and may provide a viable therapeutic approach for treatment of metastatic BC.

• Authors: Chi Yan, Jinming Yang, Nabil Saleh, Sheau-Chiann Chen, Gregory D Ayers, Vandana G Abramson, Ingrid A Mayer, Ann Richmond
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 10 (May 14 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 34069042 (Publication Type: Journal Article)

Chemical References

• Alpelisib
• copanlisib
• gedatolisib
• Immune Checkpoint Inhibitors
• Morpholines
• MTOR protein, human
• Paclitaxel
• Phosphatidylinositol 3-Kinases
• Phosphoinositide-3 Kinase Inhibitors
• Pyrimidines
• Quinazolines
• Thiazoles
• TOR Serine-Threonine Kinases
• Triazines

Topics

• Animals
• Female
• Humans
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Breast Neoplasms (drug therapy, pathology)
• Cell Line, Tumor
• Granulocytes (drug effects)
• Immune Checkpoint Inhibitors (administration & dosage, pharmacology)
• Mice, Inbred C57BL
• Molecular Targeted Therapy
• Morpholines (administration & dosage)
• Paclitaxel (administration & dosage)
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Phosphoinositide-3 Kinase Inhibitors (administration & dosage)
• Pyrimidines (administration & dosage)
• Quinazolines (administration & dosage)
• Thiazoles (administration & dosage)
• TOR Serine-Threonine Kinases (metabolism)
• Treatment Outcome
• Triazines (administration & dosage)
• Tumor Microenvironment (drug effects)
• Xenograft Model Antitumor Assays
• Mice