Fast proliferating and slowly migrating non‐small cell lung cancer cells are vulnerable 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. In our study, we test the efficacy of the DNA‐hypomethylating agent decitabine (DAC) in combination with all‐trans retinoic acid (ATRA), which 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. Transcriptomics, proteomics, proliferation and migration profiling revealed that fast proliferating and slowly migrating cell lines were more sensitive to the drug combination. The comparison of mutational profiles found oncogenic KRAS mutations only in sensitive cells. Additionally, different cell lines showed a heterogeneous gene expression response to the treatment pointing to diverse mechanisms of action. Silencing KRAS, RIG‐I or RARB partially reversed the sensitivity of KRAS‐mutant NCI‐H460 cells. To study resistance, we generated two NCI‐H460 cell populations resistant to ATRA and DAC, which 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.

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“…Acquired resistance is an urgent problem in cancer treatment, and combination therapies can help to minimize the risk of resistance. Studies have shown that the combination of decitabine and retinoic acid increases sensitivity and therapeutic efficacy in rapidly proliferating and slowly migrating NSCLC ( 10 ). The advent of targeted therapies and immunotherapy has provided a glimmer of hope for NSCLC patients.…”