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RIDR-PI-103, ROS-activated prodrug PI3K inhibitor inhibits cell growth and impairs the PI3K/Akt pathway in BRAF and

Hima Patel1, Rosalin Mishra2, Adam Wier3

  • 1UT Southwestern Medical Center, Harold C. Simmons Cancer Center, Dallas.

Anti-Cancer Drugs
|February 27, 2023
PubMed

Insights

Reactive oxygen species (ROS) levels increase in BRAF-mutant melanoma resistant to dabrafenib and trametinib. A novel ROS-induced drug release (RIDR)-PI-103 shows reduced toxicity and inhibits resistant cell proliferation, offering new therapeutic avenues.

Area of Science:

  • Oncology
  • Pharmacology
  • Biochemistry

Background:

  • Elevated reactive oxygen species (ROS) levels are observed in BRAF-mutant melanoma following resistance to BRAF inhibitors (e.g., dabrafenib) and MEK inhibitors (e.g., trametinib).
  • Trametinib and dabrafenib-resistant (TDR) melanoma cells exhibit sustained p-Akt levels and significantly higher ROS compared to parental cells.
  • Conventional PI3K inhibitors like PI-103 can cause toxicity, necessitating targeted delivery strategies.

Purpose of the Study:

  • To evaluate the efficacy and safety of a novel ROS-induced drug release (RIDR)-PI-103 in BRAF-mutant melanoma cells resistant to BRAF and MEK inhibitors.
  • To investigate the mechanism of action of RIDR-PI-103 in TDR cells, focusing on ROS-mediated drug release and downstream signaling.
  • To explore the potential of RIDR-PI-103 as a targeted therapeutic strategy for overcoming resistance in melanoma.

Main Methods:

  • Development and characterization of RIDR-PI-103, a PI-103 prodrug designed for ROS-triggered release.
  • Assessment of RIDR-PI-103 toxicity in melanocytes compared to PI-103.
  • Inhibition of TDR cell proliferation and Western blot analysis of key signaling proteins (p-Akt, p-S6) following RIDR-PI-103 treatment.
  • Mechanism of action studies using ROS scavengers (glutathione) and inducers (t-butyl hydrogen peroxide) in combination with RIDR-PI-103.

Main Results:

  • RIDR-PI-103 demonstrated reduced toxicity in melanocytes compared to PI-103 at 5 µM.
  • RIDR-PI-103 significantly inhibited TDR cell proliferation at concentrations of 5 and 10 µM.
  • Treatment with RIDR-PI-103 led to the inhibition of p-Akt, p-S6 (Ser240/244), and p-S6 (Ser235/236) in TDR cells.
  • ROS scavenging with glutathione rescued TDR cell proliferation, while ROS induction with t-butyl hydrogen peroxide enhanced RIDR-PI-103's inhibitory effect.

Conclusions:

  • RIDR-PI-103 effectively targets and inhibits the proliferation of BRAF and MEK inhibitor-resistant melanoma cells.
  • The drug's efficacy is mediated by ROS-dependent release of PI-103, leading to the suppression of key pro-survival signaling pathways.
  • RIDR-PI-103 represents a promising novel therapeutic approach for treating resistant melanoma, warranting further investigation for clinical application.

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