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EXEL-7647 inhibits mutant forms of ErbB2 associated with lapatinib resistance and neoplastic transformation

Torsten Trowe1, Sotiria Boukouvala, Keith Calkins

  • 1Exelixis, Inc., South San Francisco, CA 94083, USA.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|April 17, 2008
PubMed
Abstract

Insights

New ErbB2 mutations cause resistance to lapatinib, a targeted cancer therapy. A new drug, EXEL-7647, effectively inhibits these resistant mutations, offering a potential treatment strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Kinase inhibitors are crucial for cancer therapy, but drug resistance, often due to mutations, limits their efficacy.
  • Understanding resistance mechanisms is vital for developing more effective targeted treatments.

Purpose of the Study:

  • To prospectively identify ErbB2 mutations that confer resistance to the small-molecule inhibitor lapatinib.
  • To investigate the mechanisms underlying lapatinib resistance.
  • To evaluate the efficacy of a novel inhibitor against these resistant mutations.

Main Methods:

  • In vitro screening of a mutagenized ErbB2 expression library in Ba/F3 cells.
  • Structural computer modeling to elucidate resistance mechanisms.
  • Testing the efficacy of EXEL-7647 against resistant ErbB2 mutants.

Main Results:

  • Identified 16 distinct ErbB2 mutations conferring lapatinib resistance, with 12 in the kinase domain.
  • ErbB2 T798I mutation showed the strongest resistance, analogous to known gatekeeper mutations.
  • Mutations L755S and T733I, found in human cancers, confer lapatinib resistance.
  • The inhibitor EXEL-7647 effectively inhibited most lapatinib-resistant ErbB2 mutants.
  • No resistance to EXEL-7647 was observed in conjunction with lapatinib sensitivity.

Conclusions:

  • Identified target-based resistance mechanisms to lapatinib.
  • EXEL-7647 demonstrates potential to overcome lapatinib resistance in ErbB2-driven cancers.

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