27MO BDTX-1535, a CNS penetrant, irreversible inhibitor of intrinsic and acquired resistance EGFR mutations, demonstrates preclinical efficacy in NSCLC and GBM PDX models

Cancer Therapy: Preclinical EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors

Purpose: Mutant selective irreversible pyrimidine-based EGFR kinase inhibitors, includingWZ4002,CO-1686, andAZD9291, are effective in preclinical models and in lung cancer patients harboring the EGFR T790Mgefitinib/erlotinib resistancemutation. However, little is known about how cancers develop acquired resistance to this class of EGFR inhibitors. We sought to identify and study EGFR mutations ...

CRIPTO1 expression in EGFR-mutant NSCLC elicits intrinsic EGFR-inhibitor resistance.

The majority of non-small cell lung cancer (NSCLC) patients harbor EGFR-activating mutations that can be therapeutically targeted by EGFR tyrosine kinase inhibitors (EGFR-TKI), such as erlotinib and gefitinib. Unfortunately, a subset of patients with EGFR mutations are refractory to EGFR-TKIs. Resistance to EGFR inhibitors reportedly involves SRC activation and induction of epithelial-to-mesenc...

EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors.

PURPOSE Mutant selective irreversible pyrimidine-based EGFR kinase inhibitors, including WZ4002, CO-1686, and AZD9291, are effective in preclinical models and in lung cancer patients harboring the EGFR T790M gefitinib/erlotinib resistance mutation. However, little is known about how cancers develop acquired resistance to this class of EGFR inhibitors. We sought to identify and study EGFR mutati...

Title: The EGFR T790M mutation in acquired resistance to an irreversible second-generation EGFR inhibitor

The EGFR T790M mutation in acquired resistance to an irreversible second-generation EGFR inhibitor.

Molecular target therapies using first-generation, reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as gefitinib or erlotinib, have been shown to be effective for patients with non-small cell lung cancer (NSCLC) who harbor activating mutations in EGFR. However, these patients eventually develop resistance to the reversible TKIs, and this has led to the d...