Epigenetic adaptations in drug-tolerant tumor cells.

Traditional chemotherapy against cancer is often severely hampered by acquired resistance to the drug. Epigenetic alterations and other mechanisms like drug efflux, drug metabolism, and engagement of survival pathways are crucial in evading drug pressure. Herein, growing evidence suggests that a subpopulation of tumor cells can often tolerate drug onslaught by entering a "persister" state with minimal proliferation. The molecular features of these persister cells are gradually unraveling. Notably, the "persisters" act as a cache of cells that can eventually re-populate the tumor post-withdrawal drug pressure and contribute to acquiring stable drug-resistant features. This underlines the clinical significance of the tolerant cells. Accumulating evidence highlights the importance of modulation of the epigenome as a critical adaptive strategy for evading drug pressure. Chromatin remodeling, altered DNA methylation, and de-regulation of non-coding RNA expression and function contribute significantly to this persister state. No wonder targeting adaptive epigenetic modifications is increasingly recognized as an appropriate therapeutic strategy to sensitize them and restore drug sensitivity. Furthermore, manipulating the tumor microenvironment and "drug holiday" is also explored to maneuver the epigenome. However, heterogeneity in adaptive strategies and lack of targeted therapies have significantly hindered the translation of epigenetic therapy to the clinics. In this review, we comprehensively analyze the epigenetic alterations adapted by the drug-tolerant cells, the therapeutic strategies employed to date, and their limitations and future prospects.

Transcriptomic analysis reveals differential adaptation of colorectal cancer cells to low and acute doses of cisplatin.

Over the years, the landscape of cisplatin-based cancer treatment options has undergone continuous transitions. Currently, there is much debate over the optimum dose of cisplatin to be administered to cancer patients. In clinical practice, it can extend from repeated low sub-toxic doses to a few cycles of acute high drug doses. Herein, the molecular understanding of the overall cellular response to such differential doses of cisplatin becomes crucial before any decision making; and it has been a grey area of research. In this study, colorectal cancer (CRC) cells were treated with either- a low sub-toxic dose (LD; 30 µM) or a ten times higher acute dose (HD; 300 µM) of cisplatin, and thereafter, the cellular response was mapped through RNA sequencing followed by transcriptomic analysis. Interestingly, we observed that the tumor cells' response to varying doses of cisplatin is distinctly different, and they activate unique transcriptional programs. The analysis of differentially regulated or uniquely expressed transcripts and corresponding pathways revealed a preferential enrichment of genes associated with chromatin organization, oxidative stress, senescence-associated signaling, and developmentally-active signaling pathways in HD; whereas, modulation of autophagy, protein homeostasis, or differential expression of ABC transporters was primarily enriched in LD. This study is the first of its kind to highlight cellular transcriptomic adaptations to different doses of cisplatin in CRC cells. Consequently, since, protein homeostasis was found to be deeply affected after cisplatin treatment, we further analyzed one of the primary cellular protein homeostatic mechanisms- autophagy. It was activated upon LD, but not HD, and served as a pro-survival strategy through the regulation of oxidative stress. Inhibition of autophagy improved sensitivity to LD. Overall, our study provides a holistic understanding of the distinct molecular signatures induced in CRC cells in response to differential cisplatin doses. These findings might facilitate the design of tailored therapy or appropriate drug dose for enhanced efficacy against CRCs.