22P - Increased schedule-dependent efficiency of pemetrexed–cisplatin combination therapy eliminates resistant lung cancer stem-like cells associated wit...

Date 15 April 2016
Event European Lung Cancer Conference 2016 (ELCC) 2016
Session Poster lunch
Topics Cytotoxic agents
Thoracic malignancies
Translational Research
Basic Principles in the Management and Treatment (of cancer)
Therapy
Biological therapy
Presenter Thomas Marti
Citation Journal of Thoracic Oncology (2016) 11 (supplement 4): S57-S166. S1556-0864(16)X0004-4
Authors T.M. Marti, C.C. Tièche, R. Peng, P. Dorn, L. Froment, R.A. Schmid
  • Division Of General Thoracic Surgery, Inselspital Bern, 3010 - Bern/CH

Abstract

Background

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers, with the current standard regimen of care for NSCLC including chemotherapy with pemetrexed as a single agent or in combination with platinum-based agents, e.g. cisplatin. Pemetrexed is an antifolate agent that inhibits the synthesis of precursor nucleotides, whereas cisplatin directly induces DNA adducts, the repair of which is dependent on sufficiently high nucleotide levels. In the clinical setting, the pemetrexed–cisplatin combination therapy is administered concomitantly. We hypothesized that extended pretreatment with pemetrexed could be beneficial, as prior depletion of nucleotide pools could sensitize cancer cells to subsequent treatment with cisplatin.

Methods

NSCLC A549 cells were treated with pemetrexed for 72 hours. In addition, 24 hours of cisplatin treatment was initiated at day 1, 2 or 3 resulting in either simultaneous pemetrexed application or pemetrexed pretreatment for 24 or 48 hours, respectively. Cell growth and colony formation as well as senescence induction were quantified after treatment. Cell cycle distribution and DNA damage induction was quantified by flow cytometry.

Results

Extended pemetrexed pretreatment for 48 hours prior to cisplatin treatment maximally delayed long-term cell growth and significantly reduced the number of recovering clones. Moreover, apoptosis and senescence were augmented and recovery from treatment-induced DNA damage was delayed. Interestingly, a resistant cell population was identified that displayed an epithelial-to-mesenchymal transition and which had a stem cell phenotype.

Conclusions

Prolonged pemetrexed pretreatment optimizes the anticancer efficiency of pemetrexed–cisplatin combination therapy, therefore, this study warrants further investigations to elucidate whether such an adaptation could enhance the effectiveness of the standard clinical treatment regimen. In addition, a subpopulation of therapy resistant cells with EMT and cancer stem cell features was identified.

Clinical trial identification

Legal entity responsible for the study

N/A

Funding

Supported by the Bernese Cancer League and the Swiss Cancer Research (KFS-3530–08–2014) to TMM

Disclosure

All authors have declared no conflicts of interest.