Src inhibitors act through different mechanisms in Non-Small Cell Lung Cancer models depending on EGFR and RAS mutational status

Oncotarget. 2015 Sep 22;6(28):26090-103. doi: 10.18632/oncotarget.4636.

Abstract

Resistance to the EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, often related to Ras or secondary EGFR mutations, is a relevant clinical issue in Non-Small Cell Lung Cancer (NSCLC). Although Src TK has been involved in such resistance, clinical development of its inhibitors has been so far limited. To better define the molecular targets of the Src TKIs saracatinib, dasatinib and bosutinib, we used a variety of in vitro/in vivo studies. Kinase assays supported by docking analysis demonstrated that all the compounds directly inhibit EGFR TK variants. However, in live cells only saracatinib efficiently reduced EGFR activation, while dasatinib was the most effective agent in inhibiting Src TK. Consistently, a pronounced anti-proliferative effect was achieved with saracatinib, in EGFR mutant cells, or with dasatinib, in wt EGFR/Ras mutant cells, poorly dependent on EGFR and erlotinib-resistant. We then identified the most effective drug combinations to overcome resistance to EGFR inhibitors, both in vitro and in nude mice: in T790M EGFR erlotinib-resistant cells, saracatinib with the anti-EGFR mAb cetuximab; in Ras mutant erlotinib-resistant models, dasatinib with the MEK inhibitor selumetinib. Src inhibitors may act with different mechanisms in NSCLCs, depending on EGFR/Ras mutational profile, and may be integrated with EGFR or MEK inhibitors for different cohorts of NSCLCs.

Keywords: EGFR inhibitors; MEK inhibitors; NSCLC; Src; drug resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / metabolism
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Benzodioxoles / administration & dosage
  • Benzodioxoles / pharmacology
  • Blotting, Western
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Cetuximab / administration & dosage
  • Cetuximab / pharmacology
  • Dasatinib / administration & dosage
  • Dasatinib / pharmacology
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • Erlotinib Hydrochloride / administration & dosage
  • Erlotinib Hydrochloride / pharmacology
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mutation
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Quinazolines / administration & dosage
  • Quinazolines / pharmacology
  • RNA Interference
  • Tumor Burden / drug effects
  • Tumor Burden / genetics
  • Xenograft Model Antitumor Assays
  • ras Proteins / genetics
  • ras Proteins / metabolism*
  • src-Family Kinases / antagonists & inhibitors*
  • src-Family Kinases / genetics
  • src-Family Kinases / metabolism

Substances

  • Benzodioxoles
  • Protein Kinase Inhibitors
  • Quinazolines
  • saracatinib
  • Erlotinib Hydrochloride
  • ErbB Receptors
  • src-Family Kinases
  • ras Proteins
  • Cetuximab
  • Dasatinib