Non-small cell lung cancer cell vulnerability to decitabine and retinoic acid combinatorial treatment

Abstract: Non-small cell lung cancer (NSCLC) patients are often elderly or unfit and thus cannot tolerate standard aggressive therapy regimes, like platinum-based chemotherapy - creating a large clinical need for alternative therapy options especially for this patient group.
In this study, I tested the efficacy of the DNA-hypomethylating agent decitabine (DAC) in combination with all-trans retinoic acid (ATRA), a treatment strategy that has been shown to possess little systemic adverse effects.
Screening a broad panel of 56 NSCLC cell lines uncovered a decrease in cell viability after the combination treatment in 77% of the cell lines and 63% and 53% of the sensitive cell lines showed more than an additive effect for ATRA and DAC at high and low doses, respectively.
At the molecular level, different cell lines showed a heterogeneous gene expression response to the treatment pointing to diverse mechanisms of action. Overall, sensitive cell lines showed more than a 3-fold difference in upregulation of MAGEB2, CTAG1B, RXRG, IRF7, CD38, IFIH1 and HIC1 genes compared to non-sensitive cell lines after ATRA and DAC treatment at high dose. By performing gene set enrichment analysis using transcriptomics and proteomics datasets already available for the NSCLC cell line panel, I hypothesized that sensitive and non-sensitive cell lines had different proliferation rates and migration capabilities.
At the cellular level, proliferation and migration profiling revealed that fast proliferating and slowly migrating cell lines were more sensitive to the drug combination.
Additionally, the comparison of mutational profiles found canonical oncogenic KRAS mutations in codons 12, 13 and 61 only in sensitive cells.
In the KRAS-mutant cell line NCI-H460, which is the cell line with the strongest synergistic effect of ATRA and DAC, silencing of KRAS, RIG-I or RARB partially rescued the cell survival after ATRA and DAC treatment.
To study the possible development of acquired resistance, I treated continuously NCI-H23 and NCI-H460 cells for two months. While it was not possible to generate resistant populations for NCI-H23, for NCI-H460, I generated two cell populations resistant to ATRA and DAC treatment, which lacked the expression induction patterns seen in the parental NCI-H460 cells after treatment. Moreover, the NCI-H460 resistant populations migrated faster and proliferated slower than the parental sensitive cells and showed signs of senescence.
In summary, this comprehensive dataset uncovers a broad sensitivity of NSCLC cells to the combinatorial treatment with DAC and ATRA and indicates that migration and proliferation capacities correlate with and could thus serve as determinants for drug sensitivity in NSCLC

Angaben zum Objekt

• Standort: Deutsche Nationalbibliothek Frankfurt am Main
• Umfang: Online-Ressource
• Sprache: Englisch
• Anmerkungen: Universität Freiburg, Dissertation, 2023

Klassifikation und Themen

• Schlagwort: Nicht-kleinzelliges Bronchialkarzinom ; Therapie ; Krebs

Beteiligte, Orts- und Zeitangaben

• Ereignis: Veröffentlichung
• (wo): Freiburg
• (wer): Universität
• (wann): 2023
• Urheber: Pelos, Giulia
• Beteiligte Personen und Organisationen: Diederichs, Sven ; Diederichs, Sven ; Lübbert, Michael ; Zentrum Translationale Zellforschung ; Albert-Ludwigs-Universität Freiburg. Medizinische Fakultät

Weitere Informationen

• DOI: 10.6094/UNIFR/238242
• URN: urn:nbn:de:bsz:25-freidok-2382424
• Rechteinformation: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Letzte Aktualisierung: 25.03.2025, 13:50 MEZ