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

Int J Mol Sci. 2021 May 14;22(10):5207. doi: 10.3390/ijms22105207.

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.

Keywords: PI3K/mTOR; breast cancer; cytotoxic T cells; immune checkpoint inhibitor.

Publication types

  • Clinical Trial

MeSH terms

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

Substances

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