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A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds
Published on: April 6, 2016
Src inhibitors act through different mechanisms in Non-Small Cell Lung Cancer models depending on EGFR and RAS
Luigi Formisano1, Valentina D'Amato1, Alberto Servetto1
1Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy.
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.
Insights
Src inhibitors like saracatinib and dasatinib show promise in overcoming resistance to EGFR tyrosine kinase inhibitors (TKIs) in Non-Small Cell Lung Cancer (NSCLC). Combinations with other targeted therapies offer new strategies for treating resistant NSCLC. Keywords: NSCLC, EGFR inhibitors, Src inhibitors, drug resistance.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Resistance to EGFR tyrosine kinase inhibitors (TKIs) is a major clinical challenge in Non-Small Cell Lung Cancer (NSCLC).
- Src tyrosine kinase (TK) has been implicated in EGFR-TKI resistance, but its inhibitors have limited clinical development.
- Understanding the precise molecular targets of Src TKIs is crucial for developing effective resistance-overcoming strategies.
Purpose of the Study:
- To investigate the molecular targets and anti-cancer effects of Src TKIs (saracatinib, dasatinib, bosutinib) in EGFR-TKI resistant NSCLC models.
- To identify optimal drug combinations to overcome resistance to gefitinib and erlotinib in NSCLC.
- To elucidate the differential mechanisms of Src inhibitors based on EGFR/Ras mutational status.
Main Methods:
- In vitro kinase assays and molecular docking analysis to assess direct inhibition of EGFR TK variants and Src TK.
- Cell-based assays to evaluate EGFR and Src activation, and anti-proliferative effects in various NSCLC cell lines.
- In vivo studies using nude mice to test drug combinations in T790M EGFR and Ras mutant resistant models.
Main Results:
- Saracatinib and dasatinib directly inhibit EGFR TK variants, but only saracatinib effectively reduced EGFR activation in live cells.
- Dasatinib demonstrated superior inhibition of Src TK in live cells.
- Saracatinib showed anti-proliferative effects in EGFR mutant cells, while dasatinib was effective in wt EGFR/Ras mutant cells resistant to erlotinib.
- Effective combinations identified: saracatinib with cetuximab for T790M EGFR resistance, and dasatinib with selumetinib for Ras mutant resistance.
Conclusions:
- Src inhibitors exhibit distinct mechanisms of action in NSCLC, influenced by EGFR/Ras mutational profiles.
- Saracatinib and dasatinib represent potential therapeutic options for overcoming EGFR-TKI resistance in specific NSCLC patient cohorts.
- Combination therapies involving Src inhibitors with EGFR or MEK inhibitors offer promising strategies for managing resistant NSCLC.
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