Predictive biomarkers for response to trametinib in non-small cell lung cancer
Palak R Parekh1,2, Gregory M Botting1,2, Denise B Thurber1
1BioMarker Strategies LLC., Rockville, MD, USA.
Background:
Non-small cell lung cancer (NSCLC) is a leading cause of cancer deaths. Current companion diagnostics use driver mutation sequencing to select patients for molecularly targeted agents (MTA), even though most patients lack actionable mutations. These diagnostics utilize static biomarkers, ignoring real-time tumor cell biology.
Objective:
Trametinib is FDA-approved in combination with dabrafenib for BRAF V600E-positive NSCLC, however, it has plausible utility beyond these patients. We sought to identify novel biomarkers for maximizing trametinib application.
Methods:
Trametinib responses were evaluated in 12 EGFR/BRAF wild-type (WT) NSCLC cell lines with diverse RAS mutational status. We identified three response categories by colony assay. Trametinib-induced molecular dynamics were studied using immunoassays and apoptosis/necrosis assays, to identify predictive response biomarkers.
Results:
p27 accumulation and cyclin D1 downregulation suggested universal cell cycle arrest with trametinib. However, 4 cell lines showed PARP cleavage and 8 showed increased phospho-4E-BP1, suggesting varied cellular outcomes from apoptosis, necrosis, senescence to autophagy. Cleaved PARP, phospho-4E-BP1 and phospho-AKT expression can predict these outcomes.
Conclusions:
Trametinib monotherapy outcome may depend upon cellular context more than oncogenic mutation status. In BRAF WT NSCLC, trametinib may be best suited for combination therapy and dynamic biomarkers could select combinations and predict responses.
Insights
Trametinib shows varied effects in non-small cell lung cancer (NSCLC) beyond BRAF mutations. Dynamic biomarkers, not just mutation status, can predict patient response and guide combination therapies for NSCLC.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Non-small cell lung cancer (NSCLC) remains a major cause of cancer mortality.
- Current diagnostics for molecularly targeted agents (MTAs) rely on static biomarkers and miss patients without actionable mutations.
- Tumor cell biology dynamics are often overlooked by existing diagnostic methods.
Purpose of the Study:
- To explore the utility of trametinib beyond its FDA-approved indication for BRAF V600E-positive NSCLC.
- To identify novel biomarkers for optimizing trametinib treatment strategies.
- To investigate trametinib's effects in EGFR/BRAF wild-type (WT) NSCLC cell lines with varying RAS mutation statuses.
Main Methods:
- Assessed trametinib response in 12 EGFR/BRAF WT NSCLC cell lines using colony assays to categorize responses.
- Investigated trametinib-induced molecular changes via immunoassays and apoptosis/necrosis assays.
- Identified potential predictive biomarkers for trametinib response.
Main Results:
- Trametinib induced cell cycle arrest, evidenced by p27 accumulation and cyclin D1 downregulation.
- Diverse cellular outcomes including apoptosis, necrosis, senescence, and autophagy were observed.
- Predictive biomarkers for these varied outcomes include cleaved PARP, phospho-4E-BP1, and phospho-AKT expression.
Conclusions:
- Trametinib's efficacy in BRAF WT NSCLC may be influenced by cellular context rather than solely oncogenic mutations.
- Trametinib might be more effective in combination therapies for BRAF WT NSCLC.
- Dynamic biomarkers hold promise for selecting optimal drug combinations and predicting patient responses to trametinib.
