1. Academic Validation
  2. Novel Third-Generation EGFR Tyrosine Kinase Inhibitors and Strategies to Overcome Therapeutic Resistance in Lung Cancer

Novel Third-Generation EGFR Tyrosine Kinase Inhibitors and Strategies to Overcome Therapeutic Resistance in Lung Cancer

  • Cancer Res. 2019 Feb 15;79(4):689-698. doi: 10.1158/0008-5472.CAN-18-1281.
Ayesha Murtuza  # 1 Ajaz Bulbul  # 1 John Paul Shen 1 Parissa Keshavarzian 1 Brian D Woodward 1 Fernando J Lopez-Diaz 1 Scott M Lippman 1 Hatim Husain 2
Affiliations

Affiliations

  • 1 University of California San Diego, Moores Cancer Center, La Jolla, California.
  • 2 University of California San Diego, Moores Cancer Center, La Jolla, California. [email protected].
  • # Contributed equally.
Abstract

EGFR-activating mutations are observed in approximately 15% to 20% of patients with non-small cell lung Cancer. Tyrosine kinase inhibitors have provided an illustrative example of the successes in targeting oncogene addiction in Cancer and the role of tumor-specific adaptations conferring therapeutic resistance. The compound osimertinib is a third-generation tyrosine kinase inhibitor, which was granted full FDA approval in March 2017 based on targeting EGFR T790M resistance. The compound has received additional FDA approval as first-line therapy with improvement in progression-free survival by suppressing the activating mutation and preventing the rise of the dominant resistance clone. Drug development has been breathtaking in this space with other third-generation compounds at various stages of development: rociletinib (CO-1686), olmutinib (HM61713), nazartinib (EGF816), naquotinib (ASP8273), mavelertinib (PF-0647775), and AC0010. However, therapeutic resistance after the administration of third-generation inhibitors is complex and not fully understood, with significant intertumoral and intratumoral heterogeneity. Repeat tissue and plasma analyses on therapy have revealed insights into multiple mechanisms of resistance, including novel second site EGFR mutations, activated bypass pathways such as MET amplification, HER2 amplification, Ras mutations, BRaf mutations, PIK3CA mutations, and novel fusion events. Strategies to understand and predict patterns of mutagenesis are still in their infancy; however, technologies to understand synthetically lethal dependencies and track Cancer evolution through therapy are being explored. The expansion of combinatorial therapies is a direction forward targeting minimal residual disease and bypass pathways early based on projected resistance.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-12972
    99.21%, EGFR Tyrosine Kinase Inhibitor