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Updated: Aug 3, 2026

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
12:40

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

Published on: December 7, 2014

Enzymatic rationale and preclinical support for a potent protein kinase C beta inhibitor in cancer therapy

B A Teicher1, E Alvarez, L G Mendelsohn

  • 1Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.

Advances in Enzyme Regulation
|September 2, 1999
PubMed

Insights

The protein kinase C inhibitor LY333531 shows promise in cancer therapy. It enhanced the effectiveness of chemotherapy and radiation in preclinical models of lung and brain tumors.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Protein kinase C (PKC) signaling pathways are implicated in cancer development.
  • Selective inhibition of specific PKC isoforms may offer targeted therapeutic strategies.
  • LY333531 is a macrocyclic bisindolylmaleimide known to inhibit PKC beta 1 and beta 2 isoforms.

Purpose of the Study:

  • To evaluate the in vivo efficacy of LY333531 as a single agent and in combination with standard cancer therapies.
  • To assess the therapeutic potential of LY333531 in non-small cell lung carcinoma and glioblastoma models.

Main Methods:

  • In vivo studies using Lewis lung carcinoma and human T98G glioblastoma multiforme xenograft models.
  • Administration of LY333531 alone and in combination with paclitaxel, fractionated radiation, carboplatin, gemcitabine, and carmustine (BCNU).
  • Assessment of tumor response and animal survival rates.

Main Results:

  • LY333531 enhanced the activity of paclitaxel and fractionated radiation in Lewis lung carcinoma.
  • In T98G glioblastoma models, LY333531 combined with BCNU significantly improved tumor response and prolonged survival.
  • Combination therapy with LY333531 and BCNU led to long-term survival in 4 out of 5 animals with intracranial tumors.

Conclusions:

  • LY333531 demonstrates significant potential as an adjunct therapy in combination with established cancer treatments.
  • Selective inhibition of PKC beta isoforms may be a viable strategy for overcoming treatment resistance in lung and brain cancers.
  • Further investigation into LY333531 as a sensitizer for cytotoxic therapies is warranted.

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